Method for producing compound for inhibiting activity of SHP2

Abstract

To provide a method for producing (pharmaceutically acceptable) salts of compounds capable of inhibiting the activity of SHP2.SOLUTION: A method of making a compound of formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof, comprising reacting a compound of formula II with a compound of formula III according to the following reaction scheme: wherein A is an anion of an acid, LG is a leaving group, and n and m are integers selected from 1, 2 and 3, such that the compound of formula II is electrically uncharged.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to (pharmaceutically acceptable) salts of compounds capable of inhibiting the activity of SHP2. and polymorphs thereof, and polymorphs of the free base form of said compound, and / or said compound, The present invention relates to methods for preparing (pharmaceutically acceptable) salts and polymorphs. [Background technology]

[0002] Src homology-2 phosphatase (SHP2) regulates proliferation, differentiation, cell cycle maintenance, and migration. A non-receptor protein encoded by the PTPN11 gene contributes to multiple cellular functions, including SHP2 is a protein tyrosine phosphatase. SHP2 is a Ras mitogen-activated protein. kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways Involved in signal transduction.

[0003] Formula I [ka] (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridinyl) (4-phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro A compound named [4.5]decane-4-amine was internationally released as an inhibitor of SHP2. 2015 / 107495 A1, which further describes various treatments Methods and treatments are also described.

[0004] Src homology-2 phosphatase (SHP2) regulates proliferation, differentiation, cell cycle maintenance, and migration. A non-receptor protein encoded by the PTPN11 gene contributes to multiple cellular functions, including SHP2 is a protein tyrosine phosphatase. SHP2 is a Ras mitogen-activated protein. kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways Involved in signal transduction.

[0005] SHP2 contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic The two SH2 domains are involved in the cellular transport of SHP2. It regulates the intracellular localization and function of the phospholipase A. The molecule is composed of both N-SH2 and PTP domains. It exists in an inactive, autoinhibited conformation stabilized by a bond network involving residues For example, stimulation by cytokines or growth factors leads to exposure of the catalytic site, resulting in S This results in the enzymatic activation of HP2.

[0006] Mutations in the PTPN11 gene and subsequently SHP2 are responsible for several human diseases, e.g. For example, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, and melanoma. It has been identified in leukemia, acute myeloid leukemia, and cancers of the breast, lung, and colon. Therefore, SHP2 is a highly attractive target for the development of novel therapeutics for the treatment of various diseases. The compounds that can be prepared according to the present invention are small molecules that inhibit the activity of SHP2. Meet the need for.

[0007] The pamphlet of International Publication No. 2015 / 107495 A1 describes the following reaction scheme 1: : [ka] A process for preparing compounds of formula I, which can be characterized by:

[0008] The final compound obtained from step g above can then be synthesized by the following scheme 2: [ka] The reaction was as follows.

[0009] In this way, the compound of formula I is obtained (the last compound in Scheme 2 above). The synthesis requires at least nine steps as shown and is rather amenable to synthesis in laboratory quantities. do.

[0010] This preparation is complex, for example, the diastereomeric Furthermore, many of the intermediates do not crystallize, so they are difficult to crystallize. It must be used without utilizing higher purity based on.

[0011] Additionally, an additional chromatography step is used in this process.

[0012] Furthermore, the aldehyde starting material for the reaction in Scheme 1 above is a chemical compound known from the literature. It is a compound, but is not available in large quantities (e.g., from Aldlab Chemicals). scale), which exhibits some inherent instability, so it is best to prepare Therefore, large scale synthesis (e.g., kilogram or larger) is advantageously used. For large scale manufacturing, it is more problematic to use.

[0013] Furthermore, cyclization (step d in Scheme 1 above) can be carried out to convert the educt, the tosylate, to the desired product. However, it has only moderate yields and additional impurities are present, making separation necessary. can be.

[0014] The ketone substrate product of step e of scheme 1) is obtained by cleaving the enantiopure aldehyde starting material. Even when used, it is partially racemized and requires step f (actually two steps, aggregation and reduction) This resulted in the formation of four diastereomers in a 95:5 ratio of the two major This would result in the desired diastereomers, which would require further separation.

[0015] Furthermore, this synthesis can be carried out according to the following scheme: [ka] Many oily intermediates are required.

[0016] Therefore, although this process is easily feasible on a laboratory scale, it is difficult to achieve large-scale manufacturing. Not ideal.

[0017] The compound added in reaction b in Scheme 2 is the compound disclosed in WO 2015 / 10749 5 In the A1 pamphlet, it is obtained as "Intermediate 10" as follows. [ka]

[0018] The problem here is the relatively low yield of the amine obtained from reaction a in Scheme 3.

[0019] Furthermore, WO 2015 / 107495 A1 discloses a compound of formula I Although it is generally mentioned that a pharmaceutically acceptable salt of No clear reason or specific examples of salts are given.

[0020] Furthermore, given the many potentially salt-forming groups in Formula I, it is possible to obtain compounds with well-defined stoichiometries. It is not at all clear whether such salts can be formed. Summary of the Invention [Means for solving the problem]

[0021] In a first aspect, the present invention provides a compound of formula I as described above, or a pharmaceutically acceptable salt thereof. A method for preparing a salt, acid co-crystal, hydrate or other solvate of : [ka] wherein A is the anion of an acid, LG is a leaving group, and the compound of formula II is electrically unsaturated. wherein n and m are 1, 2, or 3, such that the compound of formula II is a charged and reacting the compound of formula III with a compound of formula III.

[0022] In a second embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino, HY is a chiral acid, and A is an acid and n and m are integers 1 to 10, so that the compound of formula II is electrically uncharged. , 2 or 3), by reacting a compound of formula IV with a compound of formula H n A to form a compound of formula I The method further comprises obtaining a compound of formula I.

[0023] In a third embodiment, the method of the present invention comprises the steps of: [ka] (wherein R1 is a protecting group for a secondary amino and HY is a chiral acid) Thus, a compound of formula V, or a salt thereof, is reacted with a chiral acid of formula HY to give a compound of formula IV. The method further includes obtaining the

[0024] In a fourth embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino and R2 is alkyl, especially tert (wherein the formula is an alkyl group) to obtain a compound of formula V. Further includes:

[0025] In a fifth embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino and R2 is alkyl, preferably t and reducing the compound of formula VII according to the method of claim 1, wherein the compound of formula VII is a tert-alkyl group, to give the compound of formula VI. It further includes obtaining things.

[0026] In a sixth embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino and R2 is alkyl, preferably t ert.-alkyl), the compound of formula VIII is reacted with the compound of formula IX reacting to obtain a compound of formula VII.

[0027] In a seventh embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino group, to obtain the compound of formula VIII.

[0028] In an eighth embodiment, the method of the present invention comprises the steps of: [ka] where R1 is a protecting group for a secondary amino, Pr1O is a leaving group, and Pr2 is a substituted silyl protecting group), to cyclize the compound of formula XI to give a compound of formula X The method further includes obtaining:

[0029] In a ninth embodiment, the method of the present invention comprises the steps of: [ka] where R1 is a protecting group for a secondary amino and Pr1O is a leaving group, particularly toluene. Pr2 is a substituted silyl protecting group, particularly a trialkyl- or diphenyl alkyl-silyl groups, in particular tert-butyldimethylsilyl), according to formula X and further comprising protecting the compound of formula II with a compound of formula PrH to obtain a compound of formula XI. nothing.

[0030] In a tenth embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino group and Ra is an unsubstituted or substituted alkyl group. Pr2 is a substituted silyl protecting group, especially a trialkyl or unsubstituted or substituted aryl group; Alkyl- or diphenylalkyl-silyl groups, especially tert-butyldimethylsilyl and reducing the compound of formula XIII to obtain the compound of formula XII according to the method described above. Further includes:

[0031] In an eleventh embodiment, the method of the present invention comprises the steps of: [ka] wherein R1 is a protecting group for a secondary amino group and Ra is an unsubstituted or substituted alkyl group. Pr2 is a substituted silyl protecting group, especially a trialkyl or unsubstituted or substituted aryl group; Alkyl- or diphenylalkyl-silyl groups, especially tert-butyldimethylsilyl A compound of formula XIV is reacted with a compound of formula XV to give a compound of formula XIII The method further includes obtaining the compound.

[0032] In a twelfth embodiment, the method of the present invention comprises the steps of: [ka] wherein Pr2 is a substituted silyl protecting group, in particular a trialkyl- or diphenylalkyl-silyl protecting group. silyl group, particularly tert-butyldimethylsilyl, where R3 is an alkyl group and R4 is and reducing the compound of formula XVI to give a compound of formula XIV according to the method of claim 1, wherein the compound of formula XVI is an alkyl group. The method further includes obtaining the

[0033] In a thirteenth embodiment, the method of the present invention comprises the steps of: [ka] wherein Pr2 is a substituted silyl protecting group, in particular a trialkyl- or diphenylalkyl-silyl protecting group. silyl group, particularly tert-butyldimethylsilyl, where R3 is an alkyl group and R4 is alkyl group, and R5 is an unsubstituted or substituted alkyl group or an unsubstituted or substituted aryl group. According to the method of the present invention, an ester compound of formula XVII is reacted with a compound of formula R4ONHR3. to obtain a compound of formula XVI.

[0034] In a fourteenth embodiment, the method of the present invention comprises the steps of: [ka] wherein Pr2 is a substituted silyl protecting group, in particular a trialkyl- or diphenylalkyl-silyl protecting group. silyl groups, particularly tert-butyldimethylsilyl, where HAL is halo and R5 is non- substituted or substituted alkyl group or unsubstituted or substituted aryl group), The compound of formula XVIII is protected with a compound of formula Pr2HAL to give a compound of formula XVII. It further includes:

[0035] In a fifteenth aspect of the present invention, in particular according to the first aspect of the present invention or according to the present invention obtainable according to any one of the second to fourteenth aspects or preferably The resulting free base form of the compound of formula I can be prepared according to the following reaction scheme: [ka] (In the formula, H r B is an acid where r is an integer, preferably 1, 2, 3 or 4 ) according to the formula H r by reaction of B with an inorganic or preferably organic acid, preferably Formula I * is converted to the acid addition salt of

[0036] In the sixteenth aspect of the present invention, the compound of formula III is preferably prepared by heating at 10° C. to 10° C. in the reaction mixture. The temperature is in the range of the boiling point of the hydrocarbon, for example, 10 to 100°C, preferably halogenated hydrocarbons, tolyl, ether or C1-C6 alkanoyl-di(C1-C6 alkyl)amide, e.g. For example, acetonitrile, dichloromethane, tetrahydrofuran or N,N-dimethylacetone in an aprotic solvent such as methyl amide, or a mixture of two or more of these solvents, Compound II: [ka] wherein LG is a leaving group, particularly halo, e.g., chloro, with a halogenating agent, e.g., a halo - halogenation with succinimide, for example bromosuccinimide, to give compounds of formula XIX: [ka] wherein LG is a leaving group, especially as defined above, and Hal is a halogen, especially bromine. which is then converted into a mercapto compound of formula XX: RO-C(=O)-CH-CH-SH (XX) wherein R6 is unsubstituted or substituted alkyl or unsubstituted or substituted aryl, particularly C 1-C6 alkyl, for example ethyl); a compound of formula XXI: [ka] wherein LG is a leaving group, R6 is unsubstituted or substituted alkyl or unsubstituted or by obtaining a substituted aryl (both preferably as defined above) The reaction is preferably carried out in an aprotic solvent, such as an ester, preferably a cyclic Esters, for example, of tertiary amines, for example diisopropylethylamine, in dioxane in the presence of a noble metal complex comprising a noble metal, particularly palladium, and a ligand such as xantphos The reaction is preferably carried out in the presence of a solvent, for example, at a temperature of from about 30°C to about the boiling point of the reaction mixture. The compound of formula XXI is then reacted with an alkali metal, in particular lithium, , potassium or most especially sodium alkoxylates, especially methoxylates or ethoxylates Upon treatment with a sylate, a compound of formula XXII: [ka] where Mt is an alkali metal, in particular as defined immediately above, is then obtained by reacting a compound of formula XXI The compound of formula I is reacted with a compound of formula XXIII. This reaction is preferably carried out over a period of about 0 to about At temperatures in the range of 50°C, alcohols such as methanol or ethanol (especially alkoxy The alkoxylate is matched with the alcohol so that the silyl group is the same as the organic group in the alcohol. solvents such as a mixture of alcohol and an ether, e.g., a cyclic ether such as tetrahydrofuran; Preferably carried out in: [ka] Compounds of Formula III: [ka] wherein LG is a leaving group as specifically defined above for compounds of formula III; Obtained.

[0037] The compound of formula XXIII is preferably prepared at low temperatures, for example in the range of about -80 to about -5°C. A strong base, especially a cyclic or especially a cyclic ether, preferably in a solvent such as tetrahydrofuran, alkyl-alkali metals, such as n-butyllithium, and nitrogen bases, especially diisopropyl In the presence of diethylamine or diethylamine, a compound of formula XXIV: [ka] can be preferably obtained by reacting with iodine.

[0038] The resulting compound of formula XXV: [ka] is treated with ammonia to give a compound of formula XXIII. Preferably, the reaction mixture is heated at a temperature ranging from about 30°C to about the boiling point of the reaction mixture, for example, from about 85°C to about 95°C. It is preferably carried out at 5°C in the presence of gaseous ammonia and an inert polar solvent such as DMSO. can be.

[0039] As an alternative to synthesis from compounds of formula XVIII, compounds of formula XIX (wherein Hal is and LG is chloro) also provides a compound of formula XXVI: [ka] with ammonia to give a compound of formula XIX (where Hal is chloro). (the reaction conditions are preferably the same as those for the reaction of the compound of formula XXV) as described immediately above), and then further via compounds of formula XXI and XXII and then reacting the compound of formula XXIII (preferably obtained as described above) with ) as described above to obtain a compound of formula III (compound and and reaction conditions, each of which are preferably as defined above as preferred).

[0040] In a seventeenth embodiment, the compound of formula XXVI described immediately above is reacted with ammonia (preferably or aqueous medium and at a temperature ranging from about 0 to about 80°C to produce a compound of formula XIX where Hal is chloro and LG is chloro, which is then reacted with a compound of the formula (Preferably anhydrous) alkali metal sulfides of MtS (where Mt is an alkali metal, especially (alk)4NZ) to form a quaternary ammonium halide compound of formula (alk)4NZ. alkoxides (wherein each alk is independently alkyl, in particular n-alkyl, e.g. C1-C6-alkyl and Z is halo, in particular chloro or more in particular bromo) By working up, a compound of formula XXVII: [ka] wherein alk is as defined immediately above, is obtained, which is then preferably is dissolved in a suitable solvent, such as water, at a temperature ranging from about −20 to about 80° C., for example, from about 0 to about 40° C. or alcohol or a mixture thereof, preferably water and / or methanol, ethanol in alcohol or, in particular, isopropanol, preferably a copper(I) iodide complex, such as CuI / In the presence of phenanthroline, a compound of formula XXIII (preferably prepared as described above) is reacted with (which can be prepared) to give a compound of formula III. [Brief explanation of the drawings]

[0041] [Figure 1]Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (1:1) hemihydrate, modified HA. [Figure 2] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine hydrochloride. [Figure 3] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine mesylate. [Figure 4] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, fumarate. [Figure 5] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine adipate (1:1), modification A. [Figure 6] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (1:1), anhydrous form, modification A. [Figure 7] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (2:1), hydrate, modified HA. [Figure 8]Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (2:1), anhydrous, modified A. [Figure 9] FIG. 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine free base modified A. [Figure 10] Figure 1 shows the XRPD of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (2:1), hydrate, modified HB. DETAILED DESCRIPTION OF THE INVENTION

[0042] definition "SHP2" means "Src homology-2 phosphatase" and SH-PTP2, SH - Also known as PTP3, Syp, PTP1D, PTP2C, SAP-2 or PTPN11 Cancers with "PTPN11 mutations" include, but are not limited to: N58 Y;D61Y, V;E69K;A72V, T, D;E76G, Q, K(ALL);G60 A;D61Y;E69V;F71K;A72V;T73I;E76G, K;R289G; G503V(AML);G60R,D61Y,V,N;Y62D;E69K;A72T, V;T73I;E76K,V,G,A,Q;E139D;G503A,R;Q506P( JMML);G60V;D61V;E69K;F71L;A72V;E76A(MDS) ;Y63C(CMML);Y62C;E69K;T507K(neuroblastoma);V46L ;N58S;E76V (lung cancer);R138Q (melanoma);E76G (colon cancer) do.

[0043] The present invention relates to all preferred compounds described in the process, particularly in embodiments A to K above. Isotopic variations are forms in which at least one atom has the same atomic number. However, the atomic masses of the atoms are different from those normally found in nature. Examples of isotopes that may be incorporated include, but are not limited to: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 35 S, 18 F, 36 Cl and 12 3 Specific isotopic variations include isotopes of hydrogen, carbon, nitrogen, and oxygen, such as I. for example, 3 H or 14 Radioisotopes such as C are incorporated into drugs and / or substrates. Useful in tissue distribution studies. In particular examples: 3 H and 14 C isotopes are In other examples, it may be used for ease of manufacture and detectability. 2 Substitution with isotopes such as H are likely to be due to higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Isotopic variations generally involve the appropriate conversion of suitable reagents. Isotopic variations may be prepared by conventional procedures.

[0044] DESCRIPTION OF THE PREFERRED EMBODIMENT The following definitions are intended to define more general features in a preferred, more specific way. , one, two or more or all of the more general features of alternative embodiments of the present invention. It is possible to substitute more specific definitions that define more specific embodiments of the invention. The same applies to the reaction embodiments described above and their preferred forms described above. This also applies.

[0045] The compounds described may be used in free form or where salt-forming groups (such as imino or amino) are present. In this case, the salt form, in particular the acid addition salt, such as a hydrogen halide, e.g., HCl, sulfuric acid or Salts with inorganic acids such as phosphoric acid, and / or sulfonic acids, e.g., methylsulfonic acid, ethylsulfonic acid, sulfonic or toluenesulfonic acids, phosphonic acids or carboxylic acids, for example alkanoic acids, It may exist as a salt with an organic acid, such as, for example, acetic acid or citric acid.

[0046] In the following, preferred conditions for the above-mentioned reactions are defined.

[0047] Reaction of compound II with a compound of formula III (reaction h), where LG is a leaving group, preferably The reaction is preferably carried out at elevated temperatures, for example at about 30° C. to about 40° C. The mixture is heated to a temperature of about 50 to about 100°C, preferably in an aprotic solvent. solvents, such as dialkylamides of N,N-alkanoic acids, e.g., dimethylacetamide or di In methylformamide, a weak base such as an alkali metal carbonate or alkali metal bicarbonate It is preferably carried out in the presence of a salt.

[0048] The reaction of the compound of formula IV with the compound of formula II (reaction i) is carried out at a temperature ranging from about 0°C to about the boiling point of the solvent. at a preferred temperature in the range of, for example, about 10°C to about 40°C (especially when R2 is acyl). , preferably a solvent, such as alcohol or alcohol, for example isopropyl alcohol and / or in a mixture of methanol and n A's (Akira (l) an organic or preferably inorganic acid, preferably trifluoroacetic acid, trifluoromethanesulfonyl Phonic acid or preferably an inorganic acid, such as sulfuric acid, phosphoric acid or especially a hydrogen halide, most especially a salt in the presence of hydrogen chloride and / or water (especially when R2 is acyl, especially lower alkanoyl, e.g. The reaction is preferably carried out in the presence of a hydroxybenzoate (e.g., acetyl).

[0049] The reaction of a compound of formula V with a chiral acid HY to give a compound of formula IV (reaction j) is preferably , at a temperature in the range of about 10°C to about the boiling point of the reaction mixture, for example, about 15 to about 75°C, It is preferably carried out in the presence of an aprotic solvent, for example a nitrile such as acetonitrile. The chiral acid HY is preferably a chiral carboxylic acid, sulfonic acid or phosphonic acid. , in particular chiral carboxylic acids having one carboxylic acid (—COOH) group, e.g., (—)- O-acetyl-D-mandelic acid, dibenzyl-D-tartaric acid, or di-para-toluoyl- R1 is preferably C1-C6 alkyloxycarbonyl, for example D-tartaric acid. tert-butoxycarbonyl, A is preferably the anion of an acid, in particular The anion of an acid as described in the paragraph immediately preceding the paragraph.

[0050] The reaction of a compound of formula VI to give a compound of formula V (reaction k) can be carried out at temperatures ranging from -50 to 30°C, e.g. For example, at a preferred temperature in the range of -30 to 10°C, in the presence or absence of water, preferably a solvent, such as an alcohol, for example an alkanol, for example methanol, ethanol or in particular Isopropanol, or esters such as alkyl alkanoates, e.g., isopropyl acetate , or mixtures thereof, acids, especially strong acids, such as inorganic acids, for example sulfuric acid, phosphoric acid or especially It is preferably carried out in the presence of a hydrohalic acid, preferably hydrochloric acid, and in the form of a salt of the acid described. The compound of formula V is then reacted with the hydroxy group of the hydroxy group of the formula V in the form of a hydroxy group, which is then reacted with the hydroxy group of the formula V in the form of a .... Alternatively, the temperature may be low, for example, in the range of -50 to 10°C, particularly -20 to 0°C, and preferably in the range of an organic solvent. In a solvent such as an ether, for example methyl tert-butyl ether, a base, for example an alkali is preferably reacted with a lithium metal hydroxide, such as LiOH, KOH or especially NaOH, to give a compound of formula V R1 is preferably C1-C6 alkyloxycarbonyl. R2 is preferably tert-butoxycarbonyl, for example tert-butoxycarbonyl. C4-C6 alkyl, for example, tert-butyl.

[0051] The reduction of a compound of formula VII to give a compound of formula VI (reaction I) is preferably carried out by, e.g. For example, at a low temperature in the range of about -78 to about 0°C, particularly about -50 to about -20°C, preferably in an organic solvent. solvents, such as alcohols, for example propanol, ethanol or especially methanol, and / or In mixtures of ethers, especially cyclic ethers, such as tetrahydrofuran, imino groups, e.g. For example, the reduction is preferably carried out using a complex hydride capable of reducing lithium borohydride. R1 and R2 are preferably as defined in the paragraph immediately preceding this paragraph. .

[0052] Reaction of a compound of formula VIII with a compound of formula IX to give a compound of formula VII (reaction The reaction mixture is heated at a temperature ranging from about 20°C to about the boiling point of the reaction mixture, for example, from about 40 to about 80°C. At low temperatures, preferably in aprotic solvents, such as ethers, e.g. cyclic ethers, especially In tetrahydrofuran, a Lewis acid, such as titanium, that activates the carbonyl for condensation - tetraisoproponate or especially titanium tetraisoproponate It is preferably carried out in the presence of tetraethanolate. 1 and R2 are preferably as defined in the two paragraphs immediately preceding this one.

[0053] The oxidation of the compound of formula X to give the compound of formula VIII (reaction n) is preferably carried out in a reaction mixture of about At a temperature in the range of -40 to about 40°C, for example, about -10 to about 30°C, preferably aprotic In a solvent such as a halogenated hydrocarbon, e.g., dichloromethane, an oxidizing agent such as TEM PO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) and bleach (especially mixtures with sodium hypochlorite or potassium hypochlorite, TEMPO and (diacetate in the presence of iodobenzene or, preferably, Dess-Martin periodinane. R1 is preferably C1-C6 alkyloxycarbonyl, for example, t It is ert-butoxycarbonyl.

[0054] The cyclization of the compound of formula XI to give the compound of formula X (reaction o) is carried out at a temperature of from about -20 to about 50°C. at a preferred temperature in the range of, for example, about -5 to about 30°C, preferably in an aprotic solvent, e.g. For example, in ethers, especially cyclic ethers such as tetrahydrofuran, a phase transfer catalyst, e.g. For example, tetraalkylammonium halides, such as tetra-n-butylammonium bromide. Preferably, the reaction is carried out in the presence of a bromine. R1 is preferably a C1-C6 alkyloxy group. carbonyl, for example tert-butoxycarbonyl, and R2 is preferably ter t-C4-C6 alkyl, for example tert-butyl, and PrO is preferably a alkyloxy or preferably perfluoroalkylsulfonyloxy, tosyloxy or mesyloxy, and Pr2 is preferably trialkyl- or diphenylalkyl- Silyl group, preferably trialkylsilyl group, more preferably trimethylsilyl, t ert-butyldiphenylsilyl, triisopropylsilyl or especially tert-butyldiphenylsilyl It is methylsilyl.

[0055] Protection of a compound of formula XII with a compound of formula PrH to give a compound of formula XI ( Reaction p) is carried out at a preferred temperature in the range of about -50 to about 50°C, for example about -10 to about 10°C, Preferably, aprotic solvents are used, such as ethers, for example cyclic ethers, for example tetrahydrofuran. in dihydrofuran, a base such as an alkali metal-bis(trialkyl-substituted silyl)amide, For example, it is preferably carried out in the presence of lithium bis(trimethylsilyl)amide. , preferably C1-C6 alkyloxycarbonyl, such as tert-butoxycarbonyl Pr1 is preferably alkyl or preferably perfluoroalkylsulfonyl. Pr2 is preferably trialkyl- or diphenyl. a trialkylsilyl group, preferably a trialkylsilyl group, more preferably a trime butylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or especially te It is rt-butyldimethylsilyl.

[0056] The reduction of the compound of formula XIII to the compound of formula XII (reaction q) is preferably carried out at a temperature of about -50 to about 50°C, for example, about 10 to about 40°C, preferably in an aprotic solvent, For example, calcium chloride in an ether, such as a cyclic ether, such as tetrahydrofuran. or reduction of the esterified carboxylic acid group to give the hydrochloride, especially in the presence of lithium borohydride. Complex hydrides that can be converted to hydroxymethyl groups, such as lithium aluminum hydride, R ed-Al (bis(2-methoxyethoxy)aluminum sodium hydride), hydride Preferably, the reaction is carried out using sodium uronide. R1 is preferably a C1-C6 alkyl. oxycarbonyl, for example tert-butoxycarbonyl, and Ra is preferably alkyl, more preferably C1-C6 alkyl, for example, ethyl; Pr2 is preferably or a trialkyl- or diphenylalkyl-silyl group, preferably a trialkyl Silyl groups, more preferably trimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, isopropylsilyl or especially tert-butyldimethylsilyl.

[0057] The reaction of a compound of formula XIV with a compound of formula XV (reaction r) to give a compound of formula XIII is Preferably, the temperature is low, for example, in the range of about -78 to about 0°C, for example, about -60 to about -18°C. Preferably, the solvent is an aprotic solvent, preferably an ether, such as a cyclic ether, especially tetrahydrofuran. In drofuran, a strong base such as lithium-bis(trimethylsilyl)amide, lithium The presence of 2,2,6,6-tetramethylpiperidine or especially lithium diisopropylamide Preferably, R1 is C1-C6 alkyloxycarbonyl, For example, tert-butoxycarbonyl, and Ra is preferably alkyl, more preferably Preferably, Pr2 is C1-C6 alkyl, for example, ethyl, and Pr2 is preferably trialkyl. - or diphenylalkyl-silyl groups, preferably trialkylsilyl groups, more preferably trimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl Or especially tert-butyldimethylsilyl.

[0058] The reaction of a compound of formula XVI to give a compound of formula XIV (reaction s) is preferably For example, at a low temperature of about -100 to about 0°C, for example, about -78 to about -50°C, preferably Protic solvents such as ethers and / or halogenated hydrocarbons, such as cyclic ethers and / or halogenated alkanes, such as tetrahydrofuran and / or dichloromethane, A reducing agent capable of reducing a hydroxylamide group to a carbonyl group, such as Re It is preferably carried out in the presence of d-Al or, in particular, lithium aluminum hydride. , preferably a trialkylsilyl group, more preferably a trimethylsilyl, tert- butyldiphenylsilyl, triisopropylsilyl or especially tert-butyldimethylsilyl Each of R3 and R4 is preferably alkyl, more particularly methyl or ethyl. Pr2 is preferably a trialkyl- or diphenylalkyl-silyl group. , preferably a trialkylsilyl group, more preferably a trimethylsilyl, tert- butyldiphenylsilyl, triisopropylsilyl or especially tert-butyldimethylsilyl It's Lil.

[0059] The reaction of a compound of formula XVII to a compound of formula XVI (reaction t) is carried out by reacting a compound of formula R-O-NH-R 4 hydrohydroxylamine compounds, wherein R3 and R4 are compounds of formula XVI: [ka] wherein Pr2 is a substituted silyl protecting group and R3 is as defined above for R4 is an alkyl group, R5 is an unsubstituted or substituted alkyl group or is an unsubstituted or substituted aryl group). Preferably, Grignard reagents of formula Org-MgX, where Org is, in particular, In the presence of isopropyl magnesium chloride, Preferably, the reaction is carried out at a temperature in the range of about -50 to about 50°C, for example, about The reaction is carried out at a temperature ranging from -20 to about 20°C. , preferably C1-C6 alkyl, such as ethyl or, in particular, methyl, and Pr2 is preferably or a trialkylsilyl group, more preferably trimethylsilyl, tert-butyl diphenylsilyl, triisopropylsilyl or especially tert-butyldimethylsilyl be.

[0060] to give a compound of formula XVII, by reacting a compound of formula XVIII with a compound of formula Pr2HAL. The reaction (reaction u) is carried out in the range of about -50 to about 50°C, particularly about -20 to about 20°C. Preferably, the solvent is an aprotic solvent, such as a halogenated hydrocarbon, especially a dihydrocarbon, at a preferred temperature of It is preferably carried out in chloromethane in the presence of a tertiary nitrogen base, such as imidazole.

[0061] Preferably, R5 is phenyl-C1-C6 alkyl or, in particular, C1-C6 alkyl. Pr2 is trimethylsilyl, tert-butyl-diphenylsilyl, triisopropyl HAL is preferably butylsilyl or, in particular, tert-butyldimethylsilyl. It is chloro or especially chloro.

[0062] acid H r B (preferably an inorganic acid, such as a hydrohalic acid (r=2), e.g., hydrochloric acid, sulfuric acid) (r=2) or phosphoric acid (r=3) or especially organic acids, such as methylsulfonic acid or Adipic acid (r=1), or especially dicarbonic acid (r=2), preferably fumaric acid, most preferably and a compound of formula I, which is preferably succinic acid. * The reaction of a compound of formula I to a compound (actually a salt) of , acetonitrile, water and / or one or more alcohols, e.g. (each optionally aqueous) Methanol, ethanol or isopropyl alcohol (or any two or three of these) The reaction is preferably carried out in a mixture of these two solvents or acetonitrile. The reaction proceeds at a temperature of about the boiling point of the reaction mixture, preferably 30 to 80°C, and preferably Thereafter, the salt is cooled to, for example, about −30 to about 30° C. Alternatively, the salt is preferably in a solvent such as an ether, for example tetrahydrofuran, at a temperature ranging from about 20 to about 70°C And acid H r It may be obtained from a suspension of a compound of formula I in the presence of B. r B is preferably , formula H n The acids A are as defined above and below, or more particularly succinic acid, hydrochloric acid, methyl The preferred acid is an acid selected from the group consisting of phenylsulfonic acid, fumaric acid, and adipic acid. The main ingredient is succinic acid.

[0063] Preferably, the compound of formula I *Each of these salts can be obtained as described below in Examples 6 to 14. This can be obtained by seeding with the corresponding salt.

[0064] The present invention also relates to the following embodiments of the present invention.

[0065] Embodiment A: The present invention also provides compounds of formula I * : [ka] (In the formula, H r B is made from succinic acid, hydrochloric acid, methylsulfonic acid, fumaric acid, and adipic acid The present invention relates to compounds or rather salts, especially in crystalline form, of Preferably succinic acid.

[0066] The ratio of free base to diacid is preferably in the range (3S,4S)-8-(6-amino No-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine: Acid (mol :mol) = 1:1 to 1:1.5, or 2:1. In the following, Formula I * The compounds are essentially named by naming the anion of the acid (e.g., succinate). and (approximately, for example, ±40%, more preferably ±35% of each second value. ) The stoichiometry is indicated in parentheses, e.g., (1:1) (which is the case for (3S,4S)-8-(6-aromatic 5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-ylamino )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (free salt One molecule of acid (e.g., succinic acid) per one (±40%, preferably ±35%) molecule of the hydroxyl group ), or for example (2:1) (which means, for example, in the case of hemisuccinate, (meaning 2 molecules of acid per 1 (±40%, preferably ±35%) molecule of "free base" be.

[0067] Formula I * When a compound of formula (I) is described, this may be determined by other means than, for example, by NMR spectroscopy as shown below. Some of the characterization methods used do not distinguish beyond true salt. The present invention relates to the salts or co-crystal forms that may be present. Preferably, the salts are as described.

[0068] Embodiment B: More preferably, a compound of formula I * The compound of formula (3S,4S)-8-(6-a 5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-ylamino )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (the compound of formula I The succinate is the free form of the compound.

[0069] Embodiment C: Most preferably, the present invention provides a method for producing a crystalline cellulose having the following 2θ values: 8.1, 16.3, 17.5 , 22.5 and 26.8. (3S,4S)-8-(6-amino- 5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3 -Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (1 :1) Hemihydrate form H A , (Formula I * (included in)

[0070] More preferably, the XRPD shows 2θ peaks as shown in the 2θ value table in Example 6, and Even more preferably, the XRPD is as shown in FIG.

[0071] (3S,4S)- with a melting point onset in differential scanning calorimetry (DSC) of 186°C 8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine (2-phenyl-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine Succinate (1:1), hemihydrate form H A (Formula I * ) is also preferred, The signatures may be used alone or in combination with the XRPD data described immediately above.

[0072] Embodiment D: The present invention also relates to, in particular, one, two, three, or more of the compounds shown in the 2θ table in Example 7. having four or more or all of the XRPD peaks, in particular an XRPD diagram as shown in FIG. , (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ]Decan-4-amine hydrochloride (Formula I * (included in)

[0073] Embodiment E: The present invention also relates to, in particular, one, two, three, or more of the compounds shown in the 2θ table in Example 8. having four or more or all of the XRPD peaks, in particular an XRPD diagram as shown in Figure 3 , (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ]decane-4-amine mesylate (Formula I * (included in)

[0074] Embodiment F: The present invention also relates to, in particular, one, two, three, or more of the compounds shown in the 2θ table in Example 9. having four or more or all of the XRPD peaks, in particular an XRPD diagram as shown in FIG. , (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ]decane-4-amine fumarate (formula I * (included in)

[0075] Embodiment G: The present invention also provides a method for producing a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, 38, 39, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 Three or more, or preferably all, of the XRPD peaks, particularly the XRPD peaks shown in FIG. by the pattern, or by the melting onset temperature in DSC of 145.3°C, or (3S,4S)-8-( 6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amineazide Pate (Formula I * (included in)

[0076] Embodiment H: The present invention also provides 14.8, 19.2, 19.7, 22.3, 24.8, 2 5.8 2θ value or one, two, three or more 2θ values ​​shown in the 2θ table in Example 11 or preferably all peaks, in particular the XRPD pattern shown in FIG. by the onset of melting in DSC at 175.5°C, or by the combination of these characteristics. (3S,4S)-8-(6-amino- 5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3 -Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (1 :1), anhydride, modification A, (formula I * (included in)

[0077] Embodiment I: The present invention also provides: or one, two, three or more of the 2θ values ​​shown in the 2θ table in Example 12. or all of the XRPD peaks, particularly the XRPD pattern shown in FIG. by a DSC melting onset temperature of 7.9°C, or by any combination of these characteristics. (3S,4S)-8-(6-amino-5-((2-amino) (3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-o 1,3-dihydroxy-8-azaspiro[4.5]decane-4-amine succinate (2:1), hydrate, Modified H A , (Formula I * (included in)

[0078] Embodiment J: The present invention also provides 4.9, 13.3, 16.4, 17.0, 19.6, 20 1, 2, or 3 with 2θ values ​​of 0.6, 23.5° or the 2θ values ​​shown in the 2θ table in Example 14. Three or preferably all peaks, particularly the XRPD pattern shown in FIG. or by a DSC melting onset of 174.0°C, or by any of these characteristics. (3S,4S)-8-(6-amino-5-( (2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl 2-oxa-8-azaspiro[4.5]decane-4-amine succinate (2:1) , anhydride, modification A, (formula I * (included in)

[0079] Embodiment K: The present invention also provides a method for producing a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39 Three or more, or preferably all, of the XRPD peaks, particularly the XRPD peaks shown in FIG. by the pattern, or by the melting onset temperature in DSC of 145.3°C, or (3S,4S)-8-( 6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine It concerns the base, especially the modification A thereof.

[0080] Embodiment L: The present invention also relates to .4.8, 12.1, 16.4, 17.0, 19.6, 2 2θ values ​​of 0.6, 23.6° or the 2θ values ​​shown in the 2θ table in Example 15, in particular , by one, two, three or more XRPD peaks having the XRPD pattern shown in FIG. or by a DSC onset temperature of 171.7°C, or by any combination of these characteristics. (3S,4S)-8-(6-amino-5-((2-amino) (3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-o 1,3-dihydroxy-8-azaspiro[4.5]decane-4-amine succinate (2:1), hydrate, Modified H B , (Formula I * (included in)

[0081] Wherever 2θ values ​​are given (as in the examples), they are used to compensate for measurement errors. ) °2θ ± 0.5 °2θ, more preferably ± 0.2 °2θ Note that if one, two, three or more XRPD peaks are listed, A form having all the peaks that can be seen is most preferred.

[0082] The present invention also relates to a compound of formula I * Compounds of: [ka] (In the formula, H r B is succinic acid (most preferred), hydrochloric acid, methylsulfonic acid, fumaric acid, and and adipic acid, more preferably an acid selected from the group consisting of any of embodiments A through K above. A salt or salt form as defined in any one of the preceding embodiments, most preferably as defined in embodiment C above. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4 -yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4. 5] Decane-4-amine monosuccinate hydrate form H A ) at least pharmacologically and a pharmaceutical composition comprising the compound of formula (I) together with an acceptable excipient.

[0083] The present invention also provides methods for preventing, inhibiting, or ameliorating disease pathology and / or symptoms, including methods for treating and / or preventing or inhibiting SHP2 activity. A method for treating a disease in an animal, particularly a human, which may be improved (especially in a person in need thereof) a therapeutically effective amount of the salt described in the preceding paragraph, alone or in combination with another anti-cancer treatment, to an animal The present invention relates to a method comprising administering the compounds of the present invention in combination, either simultaneously or sequentially.

[0084] The present invention also provides methods for treating cancer in which SHP2 activity can prevent, inhibit, or ameliorate disease pathology and / or symptoms. any of embodiments A-K above for use in a method of treating a disease in an animal. For a salt or salt form as described in any one of claims 1 to 4, the method comprises administering the salt or salt form to a warm-blooded animal, This particularly includes administration to human patients.

[0085] The present invention also provides a method for treating a variety of diseases, including those in animals, particularly humans, in which SHP activity contributes to the pathology and / or symptoms of disease. any of embodiments A-K above in the manufacture of a medicament for treating a disease in a human patient. The present invention relates to the use of a salt or salt form as described in any one of the preceding claims.

[0086] In all embodiments, succinate hydrate form H A is the most favorable salt to achieve It is a form.

[0087] In one embodiment, a compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate thereof, A method for preparing a compound or other solvate thereof, comprising the steps of: [ka] wherein A is the anion of an acid, LG is a leaving group, and the compound of formula II is electrically unsaturated. wherein n and m are integers selected from 1, 2, and 3, such that a method comprising reacting a compound of formula II with a compound of formula III.

[0088] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, HY is a chiral acid, A is the anion of the acid, and n and m are integers selected from 1, 2 and 3 such that the compound of formula I is electrically uncharged. (wherein the formula is a number), the compound of formula IV is converted into a compound of formula H n A with an acid to give a compound of formula II It further includes obtaining things.

[0089] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group and HY is a chiral acid, further comprises reacting the salt with a chiral acid of formula HY to obtain a compound of formula IV.

[0090] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group and R2 is alkyl, to prepare a compound of formula VI according to the formula reacting to obtain a compound of formula V.

[0091] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group and R2 is alkyl, and to obtain a compound of formula VI.

[0092] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group and R2 is alkyl, with a compound of formula IX to obtain a compound of formula VII.

[0093] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, to obtain a compound of formula VIII The method further includes obtaining the compound.

[0094] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, Pr1O is a leaving group, and Pr2 is a substituted silyl protecting group. cyclizing the compound of formula XI according to the method of formula (I) to obtain the compound of formula X. .

[0095] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, Pr1O is a leaving group, and Pr2 is a substituted silyl protecting group. According to the method described above, a compound of formula XII is protected with a compound of formula PrH to give a compound of formula XI. This includes obtaining a compound.

[0096] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, Ra is unsubstituted or substituted alkyl or unsubstituted or substituted aryl group and Pr2 is a substituted silyl protecting group), The method further comprises reducing the compound to obtain a compound of formula XII.

[0097] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein R1 is a protecting group, Ra is unsubstituted or substituted alkyl or unsubstituted or substituted aryl group and Pr2 is a substituted silyl protecting group), to form a compound of formula XIV reacting the resulting mixture with a compound of formula XV to obtain a compound of formula XIII.

[0098] In a further embodiment, the method comprises the following reaction scheme: [ka] (Wherein Pr2 is a substituted silyl protecting group, R3 is an alkyl group, and R4 is an alkyl group) and reducing the compound of formula XVI to obtain a compound of formula XIV according to the method of Further includes:

[0099] In a further embodiment, the method comprises the following reaction scheme: [ka] (Wherein Pr2 is a substituted silyl protecting group, R3 is an alkyl group, and R4 is an alkyl group) and R5 is an unsubstituted or substituted alkyl group or an unsubstituted or substituted aryl group. According to the method of the present invention, an ester compound of formula XVII is reacted with a compound of formula R4ONHR3. to obtain a compound of formula XVI.

[0100] In a further embodiment, the method comprises the following reaction scheme: [ka] wherein Pr2 is a substituted silyl protecting group, HAL is halo, and R5 is unsubstituted or is a substituted alkyl group or an unsubstituted or substituted aryl group), The compound of formula I may be protected with a compound of formula Pr2HAL to give a compound of formula XVII. This includes:

[0101] In another embodiment, the following reaction scheme: [ka] According to the formula H r B, in salt form or free base form, with an inorganic or organic acid of formula I is a compound of formula I * to an acid addition salt of

[0102] In another embodiment, a method for preparing a compound of formula III according to claim 1 is provided, comprising the step of: Compound VIII is reacted with a halogenating agent: [ka] wherein LG is a leaving group to produce a compound of formula XIX: [ka] wherein LG is a leaving group and Hal is a halogen, which is then converted into a compound of formula XX Mercapto compounds of RO-C(=O)-CH-CH-SH (XX) wherein R6 is unsubstituted or substituted alkyl or unsubstituted or substituted aryl. and replacing the compound of formula XXI with [ka] wherein LG is a leaving group, R6 is unsubstituted or substituted alkyl or unsubstituted or substituted aryl); and then reacting the compound of formula XXI with an alkali metal alkoxide. hydroxylate to give a compound of formula XXII [ka] wherein Mt is an alkali metal, and then reacting a compound of formula XXII with a compound of formula XXII Compound I: [ka] to produce a compound of formula III: [ka] wherein LG is a leaving group.

[0103] In another embodiment, the compound of formula XXIII: [ka] XXIV, in the presence of a strong base, [ka] with iodine to obtain a compound of formula XXV: [ka] with ammonia to obtain a compound of formula XXIII.

[0104] In another embodiment, Formula I * Compounds of: [ka] (In the formula, H rB is made from succinic acid, hydrochloric acid, methylsulfonic acid, fumaric acid, and adipic acid an acid selected from the group consisting of: .

[0105] In a further embodiment, the compound is in a crystalline form.

[0106] In another embodiment, (3S,4S)-8-(6-amino-5-( (2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl 2-oxa-8-azaspiro[4.5]decane-4-amine monosuccinate free salt It is the base.

[0107] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5]decane-4-amine succinate (1:1) hydrate form H A Yes do.

[0108] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- In a further embodiment, 8-azaspiro[4.5]decan-4-amine hydrochloride is , the compound is in crystalline form.

[0109] In a further embodiment, (3S,4S)-8-(6-amino-5-((2-amino -3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-ox sa-8-azaspiro[4.5]decane-4-amine mesylate. In the formula (I), the compound is in crystalline form.

[0110] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decane-4-amine fumarate. In some cases, the compound is in crystalline form.

[0111] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decane-4-amine adipate. In some cases, the compound is in crystalline form.

[0112] In another embodiment, (3S,4S)-8-(6-amino-5-( (2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl 1-2-oxa-8-azaspiro[4.5]decan-4-amine, succinate (1:1 )

[0113] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5]decan-4-amine, succinate (2:1) hydrate.

[0114] In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5]decan-4-amine, succinate (2:1) anhydrous.

[0115] In another embodiment, the compound of formula I according to any one of the above embodiments is * Contains compounds of It is a pharmaceutical composition.

[0116] In a further embodiment, Formula I * The compound is (3S,4S)-8-(6-amino- 5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3 -Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine succinate (1 :1) Hydrated form H A is.

[0117] In another embodiment, a method of treatment comprising the steps of: Formula I * The compounds are administered to patients in need of such treatment to treat a condition mediated by the activity of SHP2. The method comprises administering to the subject a compound of formula (I) or (II) in an amount effective for the prophylactic or therapeutic treatment of the disease or disorder.

[0118] In a further embodiment, the disease or disorder mediated by the activity of SHP2 is Nunn syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute Myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, squamous epithelial cell carcinoma of the head and neck 36. The method of claim 35, wherein the cancer is selected from cancer, gastric cancer, anaplastic large cell lymphoma, and glioblastoma. method.

[0119] In another embodiment, the compounds of the above embodiments are administered simultaneously, sequentially or separately. Formula I according to any one of * and one or more other pharmacologically active compounds, particularly antiproliferative agents It is a combination including.

[0120] Pharmacology and Usefulness Src homology-2 phosphatase (SHP2) regulates proliferation, differentiation, cell cycle maintenance, and migration. The protein tyrosine kinase 1 (PTPN11) encoded by the PTPN11 gene contributes to multiple cellular functions, including SHP2 is a Ras mitogen-activated protein kinase. , signaling through the JAK-STAT or phosphoinositol 3-kinase-AKT pathways SHP2 is involved in the signal transduction of receptors such as ErbB1, ErbB2, and c-Met. Activation of Erkl and Erk2 (Erkl / 2, Erk) MAP kinases by synkinases Mediates sexualization.

[0121] SHP2 contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic The two SH2 domains are involved in the cellular transport of SHP2. It regulates intracellular localization and function. The molecule exists in an inactive conformation and contains N-SH2 and inhibits its own activity through a binding network involving residues from both the ATP and PTP domains In response to growth factor stimulation, SHP2 interacts with Gab1 and Gab2 via its SH2 domain. When proteins such as Gab2 are docked, they bind to specific tyrosine-phosphorylated sites. This induces a conformational change that leads to SHP2 activation.

[0122] Mutations in PTPN11 are associated with Noonan syndrome, Leopard syndrome, and juvenile myelomonary syndrome. Myeloid leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancer of the breast, lung, and colon. SHP2 has been identified in several human diseases. GF-R), fibroblast growth factor (FGF-R) and epidermal growth factor (EGF-R) It is an important downstream signaling molecule for various receptor tyrosine kinases, including the receptors for SHP2 also mediates mitogenesis, which can lead to cell transformation, a prerequisite for cancer development. Important downstream signaling pathways for activation of the MAP kinase pathway Knockdown of SHP2 inhibits SHP2 mutations or EML4 / ALK rearrangements. It significantly inhibited cell growth of lung cancer cell lines bearing EGFR as well as EGFR-amplified breast and esophageal cancers. SHP2 also functions downstream of oncogenes in gastric cancer, anaplastic large cell lymphoma, and glioblastoma. It is activated in

[0123] Noonan syndrome (NS) and Leopard syndrome (LS) - PTPN11 mutations S (multiple lentigines, electrocardiogram abnormalities, interocular dissection, pulmonary artery stenosis, genital abnormalities, growth retardation, sensorineural hearing loss) ) and NS (congenital abnormalities including heart defects, craniofacial malformations, and short stature). Impairment of RAS / RAF / MEK / ERK kinases, which are required for normal cell growth and differentiation, is involved in the regulation of RAS / RAF / MEK / ERK kinases. by germline mutations in components of the mitogen-activated protein kinase pathway It is part of a family of autosomal dominant syndromes that cause In addition, it has serious effects on cardiac development, leading to valvuloseptal defects. This leads to various abnormalities, including MAPK signaling damage and / or hypertrophic cardiomyopathy (HCM). Disruption of the delivery pathway has been established as central to these disorders, with KRAS, NR2, and AS, SOS1, RAF1, BRAF, MEK1, MEK2, SHOC2, and CBL Several candidate genes along this pathway have been identified in humans, including mutations in The most commonly mutated gene in NS and LS is PTPN11 Germline mutations in PTPN11 (SHP2) are associated with NS and certain other conditions. It is seen in approximately 50% of almost all patients with LS, which shares features with NS. The Y62D and Y63C substitutions in proteins are mostly invariant and most frequently Both of these mutations affect the phosphorylation signaling pathway. A catalytically inactive conformation of SHP2 without perturbing the binding of the phosphatase to its partner Affects.

[0124] Juvenile myelomonocytic leukemia (JMML) - somatic mutations in PTPN11 (SHP 2) occurs in approximately 35% of patients with JMML, a childhood myeloproliferative disorder (MPD). These gain-of-function mutations typically occur in the N-SH2 domain or phosphatase domain. The point mutation in the enzyme domain is responsible for the catalytic domain and the N-SH2 domain. This prevents autoinhibition between the two, resulting in SHP2 activity.

[0125] Acute myeloid leukemia - PTPN11 mutations are associated with childhood myelodysplastic syndromes (MDS) and other conditions. Approximately 10% of acute leukemias; approximately 7% of B-cell acute lymphoblastic leukemias (B-ALL); and It has been identified in approximately 4% of myeloid leukemias (AML).

[0126] NS and leukemia mutations affect N-SH2 and PT in the autoinhibited SHP2 conformation. This induces changes in amino acids located at the interface formed by the P domain, resulting in the formation of inhibitory molecules. It disrupts intramolecular interactions, resulting in hyperactivity of the catalytic domain.

[0127] SHP2 is a positive regulator of receptor tyrosine kinase (RTK) signaling. RTK alterations (EGFR amp , Her2 amp , FGFR amp , Met amp , translocated / activated RTKs (i.e., ALK, BCR / ABL) in cancers Cancers that are most commonly diagnosed include esophageal cancer, breast cancer, lung cancer, colon cancer, gastric cancer, glioma, and head and neck cancer.

[0128] Esophageal cancer (or oesophageal cancer) is a type of cancer that occurs in the esophagus It is a malignant tumor of the esophagus. There are various subtypes, mainly squamous cell carcinoma (<50%) and adenocarcinoma. High expression of RTKs is observed in uterine adenocarcinoma and squamous cell carcinoma. SHP2 inhibitors may be used in innovative therapeutic approaches.

[0129] Breast cancer is the leading type of cancer and a leading cause of death in women, and patients Resistance to luminal A, luminal B, Her2-like, and triple negative There are four main subtypes of breast cancer, including basaloid / positive / positive. Triple-negative breast cancer ( TNBC (TNF-kappaB) is an aggressive form of breast cancer for which specific targeted therapies are lacking. FR) has emerged as a promising target in TNBC. As such, inhibition of EGFR may be a promising therapeutic approach in breast cancer.

[0130] Lung cancer - NSCLC is currently the leading cause of cancer-related deaths, with lung cancer (mainly adenocarcinoma and squamous cell carcinoma) Cytotoxic chemotherapy remains an important part of treatment. However, targeted therapy based on genetic alterations such as EGFR and ALK in tumors is They are more likely to benefit from the law.

[0131] Colon cancer - Approximately 30% to 50% of colorectal tumors have mutated (abnormal) KRAS. It is known that BRAF mutations occur in 10-15% of colorectal cancers. For the subset of patients whose rectal tumors have been demonstrated to overexpress EGFR, These patients show a favorable clinical response to anti-EGFR therapy.

[0132] Gastric cancer is one of the most common types of cancer. The aberrant expression of tyrosine kinases reflected thereby is known in the art. Three receptor tyrosine kinases, c-met (HGF receptor), FGF receptor 2, and e rbB2 / neu is frequently amplified in gastric cancer. Destruction of the tract may contribute to the progression of various types of gastric cancer.

[0133] Neuroblastoma is a childhood tumor of the developing sympathetic nervous system that accounts for approximately 8% of childhood cancers. Genomic alterations in the anaplastic lymphoma kinase (ALK) gene contribute to the pathogenesis of neuroblastoma. It is assumed that

[0134] Squamous cell carcinoma of the head and neck (SCCHN). High levels of EGFR expression are associated with a variety of cancers, primarily those of the head and neck. correlates with poor prognosis and resistance to radiotherapy in squamous cell carcinoma of the oral cavity (SCCHN) Blockade of EGFR signaling results in receptor stimulation, inhibition of cell proliferation, and reduction of invasiveness and metastasis. Therefore, EGFR is a key target for new anti-cancer therapies in SCCHN. It is a target.

[0135] The present invention relates to salts and salt forms of compounds capable of inhibiting the activity of SHP2.

[0136] In certain embodiments, the present invention relates to the above-mentioned methods and uses, wherein said SHP 2-mediated disorders include, but are not limited to: JMML; AML; MDS; B-ALL; neuroblastoma The cancer is selected from the group consisting of cysts, esophageal cancer, breast cancer, lung cancer, colon cancer, gastric cancer, and head and neck cancer. NS;LS;JMML;AML;MDS;B-ALL;neuroblastoma;esophageal cancer;breast cancer lung cancer; colon cancer; gastric cancer; head and neck cancer.

[0137] (In particular, Formula I * Most preferably, the method is as described in any one of embodiments A to K above. The SHP2 inhibitors of the present invention (such as those described above) may be used in combination with other pharmacologically active compounds, particularly in the treatment of cancer. or may be usefully combined with two or more other pharmacologically active compounds, such as those defined above. The compounds of formula (I), or pharmaceutically acceptable salts thereof, are useful as antiproliferative agents, such as anticancer agents or chemical agents. chemotherapeutic agents, e.g., mitotic inhibitors, e.g., taxanes, vinca alkaloids, paclitaxel docetaxel, vincristine, vinblastine, vinorelbine or vinflunine , and other anticancer drugs, such as cisplatin, 5-fluorouracil or 5-fluoro-2- Select from 4(1H,3H)-pyrimidinedione (5FU), flutamide, or gemcitabine The compounds may be administered in combination with one or more other drugs simultaneously, sequentially or separately.

[0138] Such combinations may offer important advantages in therapy, including synergistic activity.

[0139] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers (excipients) and / or The compounds described above, particularly those described in embodiments A through K above, are formulated with a diluent. The present invention provides pharmaceutically acceptable compositions comprising one or more of the salts or forms of the compounds in a therapeutically effective amount. As described in detail below, the pharmaceutical compositions of the present invention can be administered by: (1) oral administration, e.g., For example, liquids (aqueous or non-aqueous solutions or suspensions), tablets, e.g., oral, sublingual, and systemic inhalation Intended for collection, bolus, powder, granule, paste for application to the tongue; (2) Parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., (3) as a bacterial solution or suspension, or sustained release formulation; (4) topical application, e.g., applied to the skin; (4) as a cream, ointment, or sustained-release patch or spray; Internally, e.g., as a pessary, cream, or foam; (5) sublingually; (6) ophthalmically; (7) percutaneous; (8) nasal; (9) pulmonary; or (10) intrathecal. The compound may be specially formulated for administration in solid or liquid form.

[0140] Wetting agents, emulsifying agents and lubricating agents such as sodium lauryl sulfate and magnesium stearate sodium, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and fragrance agents, preservatives, and Antioxidants and antioxidants may also be present in the composition.

[0141] The formulations (pharmaceutical compositions) of the present invention can be administered orally, nasally, topically (including buccal and sublingually), directly or indirectly. Formulations include those suitable for enteral, vaginal and / or parenteral administration. Formulations are conveniently available in unit dosage forms. and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with a carrier material to produce a therapeutically effective amount will vary depending on the host being treated, particularly the dosage. The dosage form may be combined with a carrier material to produce a single dosage form. The amount of active ingredient is generally the amount of compound that produces a therapeutic effect. Of the total amount, this amount may range from about 0.1 percent to about 99 percent of the active ingredient, preferably , about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent The range is cents.

[0142] Generally, Formula I * A suitable daily dose of the compound is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, the patient will receive a dose of Formula I * Oral, intravenous, intracerebroventricular and subcutaneous doses of the compound are as indicated When used for analgesic effect, from about 0.0001 to about 100 mg per kilogram of body weight per day The range is 100mg.

[0143] Optionally, Formula I * Effective daily dose of the active compound (or any combination partner) of may be administered as 2, 3, 4, 5, 6 or more subcutaneous doses administered separately at appropriate intervals throughout the day. The dosage may be administered as a single dose, optionally in unit dosage form. The preferred administration is once a day. do.

[0144] In certain embodiments, the formulations of the present invention contain cyclodextrins, cellulose, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polymers. an excipient selected from the group consisting of: hydroxypropyl methylcellulose, ... In one embodiment, the formulation comprises a compound of formula I * The compound is orally bioavailable.

[0145] Formulations of the present invention suitable for oral administration contain a predetermined amount of a compound of formula I as the active ingredient. * Each compound Contains capsules, cachets, pills, tablets, and lozenges (flavored base, usually , sucrose and acacia or tragacanth), powder, granule, or aqueous or as a solution or suspension in a non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. as an infusion, or as an elixir or syrup, or as medicinal lozenges (gelatin (using an inert base such as ethanol and glycerol, or sucrose and acacia) and and / or may be in the form of a mouthwash, etc. * The compounds may also be administered as a bolus, electuary, or paprika. It can be administered as a single dose.

[0146] The solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules) , lozenges, etc.), in which the active ingredient (especially a salt or The salt forms may be combined with one or more pharmaceutically acceptable carriers, such as sodium citrate or phosphate. dicalcium carbonate, and / or the following: (1) a filler or extender, e.g., starch (2) cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; Combinations, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone (3) a humectant, such as glycerol; (4) a humectant, such as lysine, sucrose, and / or acacia; Disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginate (5) dissolution retarders, e.g., paraffin; (6) absorption enhancers, such as quaternary ammonium compounds and surfactants, such as porphyrins; (7) wetting agents, such as cetyl alcohol, monosodium glutamate, and sodium lauryl sulfate; glycerol stearate, and nonionic surfactants; (8) absorbents, e.g., kaoli (9) lubricants, such as talc, calcium stearate, Magnesium tearate, solid polyethylene glycol, sodium lauryl sulfate, stearyl alcohol Zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) sustained-release agents, such as either crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type include those containing lactose or milk sugar as well as high molecular weight polyethylene glycols. Filling agents in soft and hard shell gelatin capsules using excipients such as ricor etc. It can be used as such.

[0147] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, agents, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linking agents) sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets are made in a suitable machine by molding a mixture of the powdered compound moistened with an inert liquid diluent. It can be made by shaping.

[0148] The term "treatment" or "treating" specifically encompasses prophylactic, therapeutic and curative methods. It is intended that

[0149] Drug combinations The present invention relates in particular to the above-mentioned embodiments in the treatment of one or more of the diseases mentioned herein. Formula I as defined in embodiments A to K * the response to treatment can be measured, for example, by Evidenced by partial or complete elimination of one or more symptoms of a disease, up to complete cure or remission This is sometimes useful.

[0150] Formula (I * ) compounds may also be used in combination with any one or more of the following drug compounds and therapeutic agents, among others: May be used in combination: BCR-ABL inhibitors: imatinib (Gleevec®); inilotinib ( Inilotinib) hydrochloride; nilotinib (Tasigna®); dasatinib bosutinib (SKI-606); ponatinib (AP245 34); bafetinib (INNO406); danusertib (PHA-739358), A T9283 (CAS 1133385-83-7); saracatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)amino] (fluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalene 1,4-imin-9-yl]-2-oxoethyl]-acetamide (PF-0381 4735, CAS 942487-16-3).

[0151] ALK inhibitor: PF-2341066 (XALKORI®; crizotinib) 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methan 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl ) pyrimidine-2,4-diamine; GSK1838705A; and CH5424802.

[0152] BRAF inhibitor: Vemurafenib (PLX4032); L GX818 and dabrafenib.

[0153] FLT3 inhibitor - sunitinib malate (registered trademark Sutent by Pfizer) PKC412 (midostaurin); tandutinib (tan utinib), sorafenib, sunitinib, midostaurin, lestaurtinib, KW -2449, quizartinib (AC220) and crenolanib.

[0154] MEK inhibitor - trametinib.

[0155] Vascular endothelial growth factor (VEGF) receptor inhibitor: bevacizumab (Genentech / R marketed under the trademark Avastin® by oche), axitinib, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-yne Also known as dazol-6-yl]sulfanyl]benzamide, AG013736 and described in PCT Publication No. WO 01 / 002369), Brivaniv alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl- 1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4] Triazin-6-yloxy)propan-2-yl)2-aminopropanoate, BMS -582664), motesanib (N-(2,3-dihydro-3,3- Dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]- 3-Pyridinecarboxamide, PCT Publication No. WO 02 / 066470 (also known as SOM230 and described in PCT Publication No. No. WO 02 / 010192), sorafenib ( sold under the trademark Nexavar®); HER2 receptor inhibitor: trastuzumab (commercially available from Genentech / Roche) Herceptin®), neratinib (HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl yl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino ) but-2-enamide, PCT Publication No. WO 05 / 0284 43), lapatinib or lapatinib ditosylate (Gla sold under the trademark Tykerb® by xoSmithKline); Trastuzumab emtansine (known in the United States as ado-trastuzumab emtansine, trademark K adcyla) - a monoclonal antibody conjugated to the cytotoxic agent mertansine (DM1) an antibody-drug conjugate consisting of rastuzumab (Herceptin); CD20 antibody: Rituximab (trademarked Riux by Genentech / Roche) an® and MabThera®), tositumomab (Sold under the trademark Bexxar® by GlaxoSmithKline ofatumumab (trademarked Arzerra by GlaxoSmithKline) (registered trademark); Tyrosine kinase inhibitor: Erlotinib hydrochloride (Genentech / Roche) marketed under the trademark Tarceva®), linifanib (N-[4-( 3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5- (methylphenyl)urea, also known as ABT 869, obtained from Genentech. available), sunitinib malate (branded Sutent by Pfizer) bosutinib (sold under the trademark [(2,4-dichloro-5-methoxyphenyl] -6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-

[0023] quinoline-3-carbonitrile, also known as SKI-606, and is disclosed in U.S. Pat. ,780,996), dasatinib (Bristol-Myers Squibb), s Sold under the trademark Sprycel® by Squibb, Alma armala (also known as pazopanib, GlaxoSmithKline under the trademark Votrient® by Pharma, Inc.), imatinib and mesylate Imatinib (branded Gilvec® and Gleev® by Novartis) sold under the trademark ec); DNA synthesis inhibitor: capecitabine (trademark Xeloda® by Roche) Gemcitabine hydrochloride (sold by Eli Lilly and Company) under the trademark Gemzar® by Pharma), nelarabine ((2R,3 S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydrogen (hydroxymethyl)oxolane-3,4-diol, by GlaxoSmithKline and sold under the trademarks Arranon® and Atriance® ); Antitumor drug: oxaliplatin (trademark Eloxa by Sanofi-Aventis) tin® and is described in U.S. Pat. No. 4,169,846. (being used); Epidermal growth factor receptor (EGFR) inhibitor: Gefitinib (trademark I) Ressa®), N-[4-[(3-chloro-4-fluoro- (phenyl)amino]-7-[[(3''S'')-tetrahydro-3-furanyl]oxy ]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, Boehring (sold under the trademark Tovok® by Erlenmeyer Ingelheim), Tuximab (branded Erbitux by Bristol-Myers Squibb) panitumumab (sold under the trademark Vectibix by Amgen) x (registered trademark); HER dimerization inhibitor: pertuzumab (trademark Omnita by Genentech) sold under the trademark rg); Human granulocyte colony-stimulating factor (G-CSF) regulator: filgrastim (Amgen) and therefore sold under the trademark Neupogen®); Immunomodulators: afutuzumab (available from Roche®), pegfi Rugrastim (sold under the trademark Neulasta® by Amgen) ), lenalidomide (also known as CC-5013 and sold under the trademark Revlimid thalidomide (sold under the trademark Thalomid®) (having); CD40 inhibitor: dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.); Pro-apoptotic receptor agonist (PARA): dulanermin (AMG-951) also known as GABA (available from Amgen / Genentech); Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl )phenyl]-4-(methylsulfonyl)-benzamide (also known as GDC-0449) It is well known and is described in PCT Publication No. WO 06 / 028958. ru); PI3K inhibitor: 4-[2-(1H-indazol-4-yl)-6-[[4-(methyl (( ...

[0023] morpholine (also known as GDC 0941, PCT Publication No. WO 02 / 09494). 9 / 036082 pamphlet and WO 09 / 055730 pamphlet 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline- 3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl] Propionitrile (also known as BEZ 235 or NVP-BEZ 235, P CT Publication No. WO 06 / 122806 (as described in the brochure); Phospholipase A2 inhibitors: anagrelide (sold under the trademark Agrylin®) (being used); BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl- 1-Cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1 R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino] -3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (A Also known as BT-263, PCT Publication No. WO 09 / 155386 listed on the fret); Mitogen-activated protein kinase kinase (MEK) inhibitor: XL-518 (C as No. 1029872-29-4, available from ACC Corp.); Aromatase inhibitors: Exemestane (trademarked Aromasin (by Pfizer) (sold under the trademark Fema)), letrozole (sold under the trademark Fema by Novartis) ra®), anastrozole (sold under the trademark Arimidex®), (sold under trademarks); Topoisomerase I inhibitor: Irinotecan (trademark Camptos by Pfizer) ar®), topotecan hydrochloride (GlaxoSmithKline sold under the trademark Hycamtin® by ne); Topoisomerase II inhibitors: Etoposide (also known as VP-16 and etoposide phosphate) It is known and sold under the trademarks Toposar®, VePesid® and Eto pophos®), teniposide (also known as VM-26 and sold under the trademark Vumon®); mTOR inhibitor: temsirolimus (branded Torisel by Pfizer) marketed under the trademark idaforolimus (formerly deforolimus) (1R,2R,4S)-4-[(2R)-2[(1R,9S, 12S, 15R, 16E, 18R, 19R, 21R, 23S, 24E, 26E, 28Z, 30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15, 17,21,23,29,35-Hexamethyl-2,3,10,14,20-pentaoxy So-11,36-dioxa-4-azatricyclo[30.3.1.0 4,9 ]Hexatri Aconta-16,24,26,28-tetraen-12-yl]propyl]-2-methox Dicyclohexyl dimethylphosphinate, also known as AP23573 and MK8669 It is well known and is described in PCT Publication No. WO 03 / 064383. everolimus (sold under the trademark Afinitor® by Novartis) being sold); Osteoclastic bone resorption inhibitor: 1-hydroxy-2-imidazol-1-yl-phosphonoic acid ethyl) phosphonic acid monohydrate (available under the trademark Zometa® by Novartis) on sale); CD33 antibody-drug conjugate: gemtuzumab ozogamicin (Pfizer / Wy sold under the trademark Mylotarg® by eth); CD22 antibody drug conjugates: inotuzumab ozogamicin (CMC-544 and Also known as WAY-207294, Hangzhou Sage Chemical C (Available from o., Ltd.) CD20 antibody-drug conjugate: Ibritumomab tiuxetan (trademark Zevali n (registered trademark); Somatostatin analogues: Octreotide (Octreotide Also known as the acetate salt and sold under the trademarks Sandostatin® and Sandos sold under the trademark tatin LAR); Synthetic interleukin-11 (IL-11): Oprelvekin (Pfizer / Wye sold under the trademark Neumega® by th); Synthetic erythropoietin: Darbepoetin alfa (trademarked Arane by Amgen) sold under the trademark sp); Receptor activator of nuclear factor kappa B (RANK) inhibitor: denosumab (available from Amgen) and sold under the trademark Prolia®); Thrombopoietin mimetic peptibody: Romiplostim (Am Sold under the trademark Nplate® by gen; Cell growth stimulator: Palifermin (registered trademark Kepivance by Amgen) (sold under trademarks); Anti-insulin-like growth factor-1 receptor (IGF-1R) antibody: figitumumab (CP-7 51,871 (available from ACC Corp.), Robatumma Bu (CAS no. 934235-44-6); Anti-CS1 antibody: elotuzumab (HuLuc63, CAS number 915296-00-3) ; CD52 antibody: alemtuzumab (sold under the trademark Campath®) ; CTLA-4 inhibitors: tremelimumab (formerly ticilimumab, CP-675, 206) ipilim (an IgG2 monoclonal antibody available from Pfizer, known as Mab (CTLA-4 antibody, also known as MDX-010, CAS number 477202 -00-9); PD1 inhibitors: for example, those disclosed in U.S. Pat. No. 8,008,449, The disclosed sequences (or sequences substantially identical or similar thereto, e.g., U.S. Pat. No. 8, At least 85%, 90%, 90% or more of the sequences set forth in US Pat. No. 5,449,999. nivolumab (referred to herein as MDX) having a sequence with 5% or more identity Also known as -1106, MDX-1106-04, ONO-4538, and BMS0936558 CAS Registry Number 946414-94-4); see, e.g., U.S. Patent No. 8,354,5 09 and WO 2009 / 114335 pamphlet, (or sequences substantially identical or similar thereto, e.g., U.S. Pat. No. 8,239,994; see also ... ,354,509 and WO 2009 / 114335 pamphlet have at least 85%, 90%, 95% or more similarity to the sequence defined by Pembrolizumab (referred to herein as lambrolizumab, MK-34) 75, MK03475, SCH-900475 or KEYTRUDA); immunoadhesins (e.g., fused to a constant region (e.g., the Fc region of an immunoglobulin sequence) immunoadhesins comprising the extracellular or PD-1 binding portion of PD-L1 or PD-L2; Pidilizumab (CT-011; Cure Tech) is a humanized antibody that binds to PD1. G1k monoclonal antibody (Pidilizumab and other humanized anti-PD-1 monoclonals) Clonal antibodies are disclosed in WO 2009 / 101611; and and International Publication No. 2010 / 027827 and International Publication No. 2011 / 0663 AMP-224 (B7-DCIg; Amplim mune) is a PD-L2 Fc fusion protein that blocks the interaction between PD1 and B7-H1. Other PD-1 inhibitors, such as those described in U.S. Pat. No. 8,609,089, are soluble receptor agonists. The specification, U.S. Patent Application Publication No. 2010028330, and / or U.S. Patent Application Publication No. An anti-PD1 antibody disclosed in the specification of Patent Publication No. 20120114649.

[0156] PDL1 inhibitor: MSB0010718C (also known as A09-246-2; Merck ck Serono) binds to PD-L1 and is described, for example, in WO 2013 / 0179 174 (and sequences substantially identical or similar thereto, For example, the sequences defined in WO 2013 / 0179174 having a sequence that has at least 85%, 90%, 95% or more identity to Monoclonal antibodies: YW243.55.S70, MPDL3280A (Gene tech / Roche) MDPL3280A and MDPL3280B are human Fc-optimized IgG1 monoclonal antibodies that bind to Other human monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743. and U.S. Patent Application Publication No. 20120039906); ME DI-4736, MSB-0010718C, or MDX-1105 (BMS-9365 MDX-1105, also known as 59, is disclosed in WO 2007 / 005874. Antibody YW243.55.S70 is an anti-PD-Ll antibody described in FRET. It is an anti-PD-L1 described in WO 2010 / 077634. ).

[0157] LAG-3 inhibitor: BMS-986016 (also known as BMS986016; Bri Stolt-Myers Squibb is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in U.S. Patent Application Publication No. 2002 / 0129994. 011 / 0150892 specification, International Publication No. 2010 / 019570 pamphlet, and disclosed in WO 2014 / 008218.

[0158] GITR Agonists: Exemplary GITR agonists include, for example, GITR fusion proteins. Proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), e.g., U.S. Pat. 111,090, EP 090505B1, U.S. Pat. No. 8,586 ,023 specification, PCT publication number International Publication No. 2010 / 003118 pamphlet and and GITR fusion proteins described in the pamphlet of the same patent application No. 2011 / 090754. , or for example, U.S. Pat. No. 7,025,962, European Patent No. 1947183B1 No. 7,812,135, U.S. Pat. No. 8,388,967 Details, U.S. Patent No. 8,591,886, European Patent No. 1866339, P CT Publication No. International Publication No. 2011 / 028683, PCT Publication No. International Publication Publication No. 2013 / 039954, PCT Publication No. International Publication No. 2005 / 00 No. 7190 pamphlet, PCT publication number International Publication No. 2007 / 133822 pamphlet PCT Publication No. WO 2005 / 055808 Pamphlet, PCT Publication No. No. International Publication No. 99 / 40196, PCT Publication No. International Publication No. 2001 / 0 No. 3720, PCT Publication No. International Publication No. 99 / 20758, PCT Publication Number International Publication No. 2006 / 083289 Pamphlet, PCT Publication Number International Publication No. 2005 / 115451, U.S. Patent No. 7,618,632 and PCT Publication No. WO 2011 / 051726 Examples of antibodies that can be used include anti-GITR antibodies.

[0159] Histone deacetylase inhibitors (HDIs): Voninostat (Sold under the trademark Zolinza® by Merck).

[0160] Anti-CTLA4 antibodies include tremelimumab (formerly ticilimumab, CP-675, 2 06, an IgG2 monoclonal antibody available from Pfizer; and and ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 4 77202-00-9).

[0161] An anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0162] Alkylating agent: temozolomide (by Schering-Plough / Merck) (sold under the trademarks Temodar® and Temodal®), Dactinomycin (also known as actinomycin-D, sold under the trademark Cosmegen (sold under the trademark )), melphalan (L-PAM, L-sarcolysin, and Also known as phenylalanine mustard and sold under the trademark Alkeran® altretamine (also known as hexamethylmelamine (HMM) (sold under the trademark Hexalen®), carmustine (sold under the trademark BiCNU®), bendamustine (sold under the trademark Treanda®) busulfan (sold under the trademarks Busulfex® and Myleran (registered trademark), carboplatin (sold under the trademark Paraplatin (registered trademark)), Lomustine (also known as CCNU and sold under the trademark CeeNU ( Cisplatin (also known as CDDP and sold under the trademark P1 (sold under the trade names Platinol® and Platinol®-AQ) , chlorambucil (sold under the trademark Leukeran®), cyclophosphamide, Famid (sold under the trademarks Cytoxan® and Neosar®) dacarbazine (also known as DTIC, DIC, and imidazole carboxamide) and sold under the trademark DTIC-Dome®), altretamine (Hexanediol Also known as hexamethylmelamine (HMM) and sold under the trademark Hexalen® Ifosfamide (sold under the trademark Ifex®), protease inhibitor rocarbazine (sold under the trademark Matulane®), mechlorethamine (nitrogen mustard, mustine and mechlorethamine Methylamine) hydrochloride, sold under the trademark Mustargen® (sold under the trademark Zanosar®), streptozocin (sold under the trademark Zanosar®), Otepa (also known as thiophosphoamide, TESPA, and TSPA, under the trademark Thio sold under the trademark plex®; Biological response modifier: Bacillus Calmette-Guerin (trade names: theraCys® and T ICE® BCG), denileukin diftitox (trademark On sold under the trademark tak); Antitumor antibiotics: doxorubicin (trade names Adriamycin® and Rub) bleomycin (sold under the trademark lenoxane) (sold under the trademark)), daunorubicin (daunorubicin Also known as daunomycin hydrochloride, daunomycin, and rubidomycin hydrochloride, and sold under the trademark Ceru Daunorubicin liposome (sold under the trademark Daunorubicin) Synthetic citrate liposomes (sold under the trademark DaunoXome®), Mitoxantrone (also known as DHAD and sold under the trademark Novantrone®) ), epirubicin (sold under the trademark Ellence™) , idarubicin (trade name Idamycin®), Idamycin PFS (registered trademark) Mitomycin C (sold under the trademark Mutamycin®) on sale); Anti-microtubule agents: estramustine (sold under the trademark Emcyl®); Cathepsin K inhibitors: odanacatib (MK-0822, N-(1-cyanocyclopropyl) (Iron)-4-fluoro-N 2 -{(1S)-2,2,2-trifluoro-1-[4'-(methyl Also known as {(4-methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide Lanzhou Chon Chemicals, ACC Corp., and Ch Available from emieTek and PCT Publication No. WO 03 / 075836 (as stated in the pamphlet).

[0163] Epothilone B analogue: ixabepilone (Bristol-Myers Squibb) therefore sold under the trademark Lxempra®); Heat shock protein (HSP) inhibitor: Tanespimycin (17-allylamino-1 Also known as 7-demethoxygeldanamycin, KOS-953, and 17-AAG , available from SIGMA and described in U.S. Pat. No. 4,261,989. (There are); TpoR agonist: Eltrombopag (commercially available from GlaxoSmithKline) (sold under the trademarks Promacta® and Revolade®) ; Antimitotic agent: docetaxel (trademark Taxot by Sanofi-Aventis) sold under the trademark ere); Adrenal steroid inhibitors: aminoglutethimide (sold under the trademark Cytadren®) being sold); Antiandrogen: Nilutamide (trade names Nilandron® and Anandr®) on®), bicalutamide (brand name Casodex® (sold under the trademark Fulexin®), flutamide (sold under the trademark Fulexin®); Androgen: Fluoxymesterone (sold under the trademark Halotestin®) being); Proteasome inhibitor: bortezomib (sold under the trademark Velcade®) (There are); CDK1 inhibitors: Alvocidib (flovopirdol or H MR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S, It is also known as 4R)-3-hydroxy-1-methyl-4-piperidinyl-4-chromenone. known and described in U.S. Pat. No. 5,621,002); Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate Iprolide (branded Viadure® by Bayer AG, Sanofi - Eligard® by Aventis and Abbott Labs marketed under the trademark Lupron®); Taxane antitumor agent: Cabazitaxel (1-hydroxy-7β,10β-dimethoxy-9 -Oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl-4 -acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butanoate (oxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), Larota Kisel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetylacetonate) 13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino] hydroxy-9-(2-hydroxy-3-phenylpropanoyl)oxy)-1- ... 5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate to); 5HT1a receptor agonist: Xaliproden (SR57746, 1-[2-(2-naphthyl) [3-(trifluoromethyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrafluoroethylene Also known as tetrahydropyridine and described in U.S. Pat. No. 5,266,573 being); HPC vaccine: Cerva marketed by GlaxoSmithKline rix®, Gardasil® marketed by Merck ; Iron chelators: Deferasirox (by Novartis) sold under the trademark Exjade®); Antimetabolites: Cladribine (trade name leustatin) 2-chlorodeoxyadenosine (sold under the trademark A), 5-fluorouracil (sold under the trademark A) drucil®), 6-thioguanine (sold under the trademark Purinet hol®), pemetrexed (sold under the trademark Alimta®), ), cytarabine (also known as arabinosylcytosine (Ara-C) and sold under the trademark Cytosar-U®), cytarabine liposomes (also known as liposomal Ara-C and sold under the trademark DepoCyt™) decitabine (sold under the trademark Dacogen®), hydroxybenzoates Hydrea (trade names: Hydrea®, Droxia®, and Mylocel®) fludarabine (sold under the trademark Fludara®) Floxuridine (sold under the trademark FUDR®), Cladri 2-chlorodeoxyadenosine (2-CdA) is also known as 2-chlorodeoxyadenosine (2-CdA) and is sold under the trademark Leus methotrexate (sold under the trademark amethopterin, methotrexate) Also known as methotrexate sodium (MTX) and sold under the trademark Rheumatrex and Trexall®), pentostatin (branded Nipen®), sold under the trademark t); Bisphosphonates: Pamidronate (sold under the trademark Aredia®) ), zoledronic acid (sold under the trademark Zometa®); Demethylating agent: 5-azacytidine (sold under the trademark Vidaza®) , decitabine (sold under the trademark Dacogen®); Plant alkaloid: protein-bound paclitaxel (trade name Abraxane®) )), vinblastine (vinblastine sulfate, vincaleucoblastine and VLB, and is sold under the trademarks Alkaban-AQ® and Velba n®), vincristine (vincristine sulfate, LCR, and Also known as VCR and sold under the trademarks Oncovin® and Vincasar®. Pfs®), vinorelbine (trade name Navelbine®), paclitaxel (sold under the trademarks Taxol and Onxal®); on sale); Retinoid: Alitretinoin (sold under the trademark Panretin®) ), tretinoin (also known as all-trans retinoic acid, ATRA, trademark V esanoid®), isotretinoin (13-cis-isotretinoin), Nonic acid, trademarks Accutane®, Amnesteem®, Cl aravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane® ), Isotret®, and Sotret®), bexarotene (sold under the trademark Targretin®); Glucocorticosteroids: Hydrocortisone (cortisone, hydrocortisone sodium) Also known as Musuccinate, Hydrocortisone Sodium Phosphate, trademark Ala- Cort®, hydrocortisone phosphate, Solu-Cortef® , Hydrocort Acetate® and Lanacort® (sold in Japan), dexamethasone (8S, 9R, 10S, 11S, 13S, 14S ,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxy acetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,1 3,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene -3-one), prednisolone (trade names Delta-Cortel®, Orap red®, Pediapred® and Prelone® (sold by Pharmacy, Inc.), prednisone (trade name Deltasone®, Liqui d Red®, Meticorten® and Orasone® (sold under the trademark), methylprednisolone (6-methylprednisolone, methyl acetate) Also known as methylprednisolone, sodium succinate, commercially available Trademarks: Duralone®, Medralone®, Medrol® Registered trademark), M-Prednisol® and Solu-Medrol® ) sold at); Cytokine: Interleukin-2 (also known as aldesleukin and IL-2) and sold under the trademark Proleukin®), interleukin-1 1 (also known as oprevelkin, trademark Neumega (sold under the trademark alpha interferon alpha (also known as IFN-α) and sold under the trademarks Intron® A and Roferon-A® (having); Estrogen receptor down-regulator: Fulvestrant (trade name Faslodex® ) sold); and LSZ102; Anti-estrogen drugs: tamoxifen (sold under the trademark Novaldex®) (There are); toremifene (sold under the trademark Fareston®); Selective estrogen receptor modulators (SERMs): Raloxifene (trade name Evista) (registered trademark); Luteinizing hormone-releasing hormone (LHRH) agonist: Goserelin (trade name Zolad) ex (registered trademark); Progesterone: Megestrol (also known as megestrol acetate, trade name Me sold under the trademark gace®); Various cytotoxic agents: arsenic trioxide (sold under the trademark Trisenox®) ), asparaginase (L-asparaginase, Erwinia sp. L- Also known as asparaginase and sold under the trademarks Elspar® and Kidrol sold under the trademark ase); Formula (I * ) may also be used in combination with the following adjunctive therapies: Antiemetic: NK-1 receptor antagonist: Casopitant (GlaxoSmithKline) Sold under the trademarks Rezonic® and Zunrisa® );and Cytoprotective agents: amifostine (sold under the trademark Ethyol®), Leu Covorin (also known as calcium leucovorin, citrovorum factor, and folinic acid) (This is the case.)

[0164] Immune Checkpoint Inhibitors: In one embodiment, the combination therapy disclosed herein and inhibitors of immune checkpoint molecules. The term refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These genes can effectively act as a "brake" to downregulate or inhibit anti-tumor immune responses. Checkpoint molecules include, but are not limited to, those that directly inhibit immune cells, mucin death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H 4, OX-40, CD137, CD40, and LAG3, and in the method of the present invention Immunotherapeutic agents that can act as useful immune checkpoint inhibitors include, but are not limited to: However, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BT Inhibitors of LA, TIGIT, LAIR1, CD160, 2B4 and / or TGFR β Inhibition of inhibitory molecules can be achieved by inhibition at the DNA, RNA, or protein level. In embodiments, an inhibitory nucleic acid (e.g., dsRNA, siRNA, or sh In another embodiment, the inhibitory molecule (RNA) can be used to inhibit expression of the inhibitory molecule. Inhibitors of a signal are polypeptides, e.g., soluble ligands, or is an antibody or an antigen-binding fragment thereof.

[0165] In certain embodiments, the compound of formula I described herein * The anti-PD-1 molecule one or more other inhibitors of PD-1, PD-L1 and / or PD-L2 known in the art The antagonist may be administered in combination with an antibody, an antigen-binding fragment thereof, or an immunoglobulin. It may be a noadhesin, a fusion protein, or an oligopeptide. [Example]

[0166] The following examples, which are also specific embodiments of the present invention, are provided by the methods defined herein. Unless otherwise specified, they serve to illustrate the present invention without limiting its scope. Ac (acetyl or acetate); ACN (acetonitrile); Boc (tert-butyl ether) toxycarbonyl); brine (saturated sodium chloride solution at room temperature); Bu (butyl); Dba (dibenzylideneacetone); DCM (dichloromethane); DIPEA (di(isopropyl ether) (propyl)ethylamine);DMAc (N,N-dimethylacetamide);DMP (des Martin periodinane; DMSO (dimethyl sulfoxide); Dppf (diphenyl ether) Nylphosphino; EA (Ethyl Acetate); ee (Enantiomeric Excess); Ent (Enantiomer) Eq or eq (equivalent); Equiv (equivalent); Et (ethyl); GC (gas chromatography) hr (hours); HPLC (high performance chromatography); IPA (isopropyl alcohol) Isopropyl alcohol; IPAc (isopropyl acetate); IT (internal temperature (in the reaction mixture)); L (liter); LDA (lithium diisopropylamide); LiHMDS (lithium biphenylsulfonyl methyl ... (trimethylsilyl)amide; LOQ (Lower limit of quantitation); Me(methyl); Me-THF (2-Methyltetrahydrofuran);MTBE (Methyl tert-butyl ether);N BS (N-bromosuccinimide); NMR (nuclear magnetic resonance); qnmr (quantitative NMR); i Pr or IP (isopropyl); PSC-1, 2, etc. (process steering control Roll (Process steering control)-1); Rt or RT( Room temperature (approximately 20 to 23°C); sat (saturated (at room temperature)); TBS (tert-butyl-2-methylbutyric acid) Methylsilyl; TBSCl (Tert-butyldimethylsilyl chloride); THF (Tet tetrahydrofuran); TLC (thin layer chromatography); TsCl (tosyl chloride); V (volume); and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethicone) ruxanthen).

[0167] Testing Procedure: XRPD (X-ray powder diffraction) data was acquired using the reflectance mode as follows: The folded pattern was analyzed in reflectance mode using a zero background SI-sample holder. Samples were acquired on a Ruker D8 Advance system. The data were collected at room temperature without rotation, with a step width of 0.017° and a step time of 0.3 seconds. The diffraction peak positions were recorded using the system evaluation software. Calculations were performed using the software.

[0168] DSC (differential scanning calorimetry) / TGA (thermogravimetric analysis) data were obtained as follows: Thermal analysis was performed using DSC or TGA. The DSC and TGA systems were TA-I For DSC, approximately 2-4 mg of The samples were prepared in aluminum crucibles with pinhole lids. Heating was at 10°C / min. Using this rate, the thermal behavior was determined from 30°C to 300°C. The same heating rate and temperature range were used. TGA is applied, whereby approximately 5-15 mg of sample is robotically The sample was filled into a sealed aluminum crucible that had been automatically pierced by an autosampler. The associated onset of melting and enthalpy and weight loss were determined using the system evaluation software. It was decided that

[0169] DVS (Dynamic Vapor Sorption) data were obtained as follows: Dynamic Vapor Sorption was calculated using the SM The analysis was carried out using the S Advantage system. Approximately 10 mg of sample was heated at 25°C for 0 The samples were exposed to various humidity levels ranging from 90% RH to 95% RH. The evaluation was performed using the system software. went.

[0170] Example 1 The compound of formula I ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) Lysin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azas Synthesis of pyro[4.5]decane-4-amine: The total synthesis can be represented by the following Reaction Scheme A: [ka] [ka]

[0171] Process a [ka] A solution of A1 (10.4 kg, 100 mol, 1.0 equiv) in CH2Cl2 (50 L) To the mixture was added imidazole (8.16 kg, 120 mol, 1.2 equivalents) and TBSCl (18 kJ / L). g, 120 mol, 1.2 eq) was added at 0° C. After the addition, the mixture was stirred at 0° C. for 4 h. GC showed that the reaction was complete (A1 / (A1+A2)<1%). The mixture was quenched with saturated NaHCO3 (14 L) at 0-5 °C. The phases were separated. The organic layer was washed with brine (14 L). The organic layer was dried over Na2SO4 and stirred at 40-45 °C. Concentration under reduced pressure gave A2 (23.3 kg, 88% assay, 94% yield), which was Used directly in the next step. 1 H NMR (400MHz, CDCl3)δ=4.35(d ,J=8.8Hz, 1H), 3.74(s,3H), 2.48(s,J=8.8Hz, 3 H), 0.93(s,9H), 0.09(s,6H).

[0172] Process b [ka] A2 (7.5 kg, 34.3 mol, 1.0 equiv) and N,O- Dimethylhydroxylamine hydrochloride (6.69 kg, 68.6 mol, 2.0 equiv.) The solution was heated at 0°C under N2 for 5-6 hours with chloro(isopropyl)magnesium (2 A solution of 1000mg Mg, 51.45 L, 3.5 equiv. was added dropwise. After the addition, the reaction mixture was cooled to 0°C. The mixture was stirred at rt for 1 h, and GC showed that the reaction was complete (A2 / (A2+A3)<2%). The mixture was slowly quenched with NH4Cl (25 L) by maintaining the temperature at 0-5 °C. After the addition, the reaction mixture was stirred for 30 min. The phases were separated. The aqueous layer was diluted with EA (2 The combined organic phase was washed with brine (25 L) and extracted with Na2SO4 The mixture was dried over ice and concentrated to give A3 (9.4 kg, assay 86%, yield 95%). This was used directly in the next step. 1H NMR (400 MHz, CDCl) δ = 4.67 (m,J=6.6Hz, 1H), 3.70(s,3H), 3.21(s,3H), 3.1 7(d,3H)2.48(s,J=6.6Hz,3H), 0.90(s,9H), 0.1 0(s,3H), 0.08(s,3H).

[0173] Process c [ka] A3 (7.1 kg, assay 86%, 24.65 mol, 1.0 L) in DCM (30 L) eq.) was added to a solution of LiAlH4 (2.4 M, 11.3 L, 1.1 eq.) at -70 °C under N2. The reaction mixture was then stirred at -70°C for 3 hours, and TLC showed The reaction was shown to be complete (PSC-1). The mixture was warmed to 0° C. and then added to saturated The mixture was quenched with potassium sodium tartrate (35 L). After the addition, DCM (20 L) was added. The mixture was stirred at 20-25°C for 2 hours. The phases were separated. The aqueous layer was extracted with DCM (25 L). The combined organic phase was charged with saturated citric acid (45 L) and stirred at 0°C for 8 hours. The phases were separated. The organic phase was washed with NaHCO3 (25 L), brine (25 L) and Na2 After drying over SO4, the solvent was removed under reduced pressure at 25-30°C. The residue was added with n-heptane (10 L) and concentrated under reduced pressure at 30-35°C. The residue was added and concentrated under reduced pressure at 30-35°C to give A4 (4.2 kg, assay 60%, A 54% yield was obtained which was used directly in the next step.

[0174] Process d [ka] Diisopropylamine (3.06 kg, A solution of 12.12 n-BuLi (30.3 mol, 1.5 equiv.) was added to 2.5 M n-BuLi (12.12 L, 30.3 mol, 1.5 eq) was added to the resulting mixture, which was stirred at about -10°C for 30 minutes. A5 (5.2 kg, 20.20 mol, 1.0 equiv.) in THF (10 L) After the addition, the reaction mixture was stirred at -10°C for 30 minutes, and then The mixture was cooled to -50°C. A4 (4.18 kg, 22.22 mol, 1.1 equiv) was added dropwise. After the addition, the reaction mixture was stirred at -50°C for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl (30 L) and water (10 L). Warmed to 25°C. The phases were separated. The aqueous phase was extracted with EA (3 x 20 L). All organic phases were combined and washed with brine (20 L), then concentrated to a yellow oil, which was Column (silica gel, 100-eluted with 50:1 to 10:1 n-heptane:EA) 200 mesh) to give A6 (5.5 kg, assay 90%, yield 55%) was obtained as a pale yellow oil. 1 H NMR (400MHz, CDCl3)δ=4.35-4 .15(m,2H), 3.95-3.74(m,3H), 3.52(m,2H), 2.6 7(m,2H), 2.12-1.98(m,2H), 1.75-1.52(m,4H), 1.49(s,9H), 1.35-1.10(m,6H), 0.98(s,9H), 0. 02(s,6H).

[0175] Process e [ka] To a solution of A6 (11.4 kg, 25.58 mol, 1.0 equiv) in THF (60 L) LiBH4 (836 g, 38.37 mol, 1.5 equivalents) was added little by little at 5-10°C. The reaction mixture was stirred at 20-25°C for 18 hours. HPLC showed the reaction was complete. (A6 / (A6+A7)<2%). The mixture was cooled to 10°C and stirred vigorously. Quenched slowly with saturated NaHCO3 solution (15 L) and water (25 L). Gas formation After the reaction stopped, vacuum filtration was applied to remove the solids. The solids were washed with EA (2 x 15 L). The phases were separated; the aqueous phase was extracted with EA (3 x 15 L). All organic phases were combined. , washed with brine (15 L) and concentrated to give crude A7 (13.8 kg, assay 58%, yield 7%). 7%) which was used directly in the next step.

[0176] process f [ka] A7 (8 kg, 19.82 mol, 1.0 equiv.) in THF (40 L) under nitrogen atmosphere ) at 10-15 °C, TsCl (5.28 kg, 27.75 mol, 1.4 equiv.) After the addition, the mixture was cooled to 0°C and 1M LiHMDS (29.7 L, 29. (73 mol, 1.5 eq) was added dropwise over a period of 2 h. After the addition, the mixture was cooled to 0°C. Stirred for 3 hours. HPLC showed the reaction was complete (PSC-1 A7 / (A7 +A8)<7%). TBAF (20.72 kg, 65.67 mol, 3.3 equiv.) was heated at 0°C. The reaction mixture was stirred at 25-30°C for 48 hours. HPLC showed that the reaction was complete. (PSC-2, A9-intermediate / (A9-intermediate + A9)<2%). The mixture was quenched with saturated aqueous sodium bicarbonate (32 L) and stirred at 0° C. for 30 minutes. The phases were separated and the aqueous phase was extracted with EA (3 x 20 L). The combined organic phases were washed with brine. (20 L), dried over Na2SO4 and concentrated to a yellow oil, which was Purification by column (eluted with 10:1 to 1:1 n-heptane:EA) gave A9 (4.42 kg, 90% assay, 74% yield) was obtained as a pale yellow solid.

[0177] Process g [ka] A9 (4.0 kg, 14.74 mol, 1.0 mL) in DCM (40 L) cooled on an ice bath To a solution of 0 equiv. DMP (9.36 kg, 23.58 mol, 1.6 equiv.) was added in small portions. After the addition, the mixture was stirred at 20-25°C for 4 hours. HPLC showed the reaction was complete (A9 / (A9+A10)<2%). M (30 L) was added at 0°C. After the addition, the mixture was washed with saturated aqueous Na2SO3 (20 L). The mixture was stirred at 0° C. for 30 min, filtered, and the white solid was dissolved in DCM (2×15 The phases were separated and the organic phase was cooled to 0°C and washed with saturated aqueous NaHCO3. (20 L) was added and stirred for 1 h. The phases were separated and the organic phase was washed with brine (25 L) and The solution was dried over a2SO4 and concentrated to a yellow oil, which was then purified by column chromatography (50:1-10 Purification by column chromatography (eluted with n-heptane:EA at 1:1 ratio) gave A10 (3.70 kg, The product was obtained as a white solid (assay 88%, ee value 95.3%, yield 82%). 1 H NMR (400MHz, DMSO-d6)δ=4.20(d,J=8.0Hz, 1H), 3.9 8-3.67(m,4H), 3.08-2.90(m,2H), 1.54-1.39(m ,13H), 1.18(d,J=8.0Hz,3H).

[0178] Process h [ka] A solution of A10 (4.60 kg, 17.08 mol, 1.0 equiv) in THF (40 L) Ti(OEt)4 (15.58 kg, 68.32 mol, 4.0 equiv.) and (R)- t-Butylsulfinamide (4.14 kg, 34.16 mol, 2.0 equiv.) was heated at 25°C. After the addition, the mixture was heated to 70° C. and stirred for 20 hours. HPLC showed that the reaction The mixture was shown to be complete (PSC-1, A10 / (A10+A12)<4%). Cool to 30 to -40°C, add MeOH (4 L) dropwise within 30 minutes, and stir for 1 hour. A 2M LiBH4 solution (8.1 L) was added dropwise to the reaction mixture at -40 to -50°C. The mixture was added and stirred for 1 hour. HPLC showed that all of the imine was consumed (PSC- 2. A12 / (A12+A13)<1%). The mixture was warmed to -30°C and stirred for 1 hour. Warm to 0°C within 2 hours, stir for 1 hour, then warm to 20-25°C and stir for 30 minutes. IPAC (25 L) was added to the above mixture, and NaHCO3 (5 L) was added at 25°C. The mixture was added dropwise over about 1 hour and stirred for 30 minutes. The mixture was filtered under reduced pressure and the cake was washed with IPA. The combined organic phase was washed with brine (25 L) and then with HCl (8 x 15 L). Evaporation under reduced pressure gave a solution of A13 (approximately 28 kg) which was used in the next step.

[0179] Process i [ka] To a mixture of A13 in IPAC (approximately 28 kg, 17.08 mol, 1.0 equiv.), -5 Add 4M HCl / IPA (8.54 L, 34.16 mol, 2.0 equiv.) dropwise at 10°C. The mixture was stirred at -5°C for 5 hours. HPLC showed that A13 was completely consumed (A 13 / (A14+A13)<1%. MTBE (25L) was added to the above mixture within 30 minutes. and stirred at -5°C for 30 minutes. The solid was collected by vacuum filtration. The cake was diluted with MTB E (2 x 2.5 L). The wet cake was used directly in the next step.

[0180] Process j [ka] Wet solid A14 (from 9.2 kg of A10) was dissolved in MTBE (76 L) at 25°C. Stir, then add 16% NaOH (9.84 kg) solution while maintaining the temperature at <10°C. The MTBE suspension was added dropwise. After the addition, the mixture was stirred for 15 minutes and all solids were removed. The organic phase was separated and the aqueous phase was extracted with MTBE (2 x 20 L). The combined organic phase was washed with brine (10 L) and evaporated under reduced pressure to remove all MTBE. ACN (24 L) was added to the above residue, and the mixture was evaporated under reduced pressure to remove the organic solvent. Stripped to give crude A15 (5.42 kg, qnmr 90%, 18.04 mol, 1.0 equiv.) ACN (34.68 kg) was added to the above residue and stirred at 65°C for 10 minutes. (-)-O-acetyl-D-mandelic acid (3.15 kg, 16 A solution of 1.2 mol, 0.9 eq) was added dropwise to the mixture over a period of 3 hours (first 1 (3) was added and stirred for 0.5 hours, then the others were added. The mixture was stirred at 65°C for 1 hour. The mixture was then cooled to 25° C. over 4 hours and stirred at 25° C. for 12 hours. The solid was vacuum filtered. The cake was collected by filtration and resuspended in pre-chilled ACN (2 x 15 kg) (PSC-1). Washing and drying under reduced pressure gave A16 (7.36 kg, 46% yield from A10 to A16). ) was obtained. 1 H NMR (400MHz, DMSO-d6)δ=7.43-7.29(m ,5H), 5.58(s,2H), 4.12-4.07(m,1H), 3.75-3.6 5(m,3H), 3.51-3.49(m,1H), 3.18-3.17(m,1H), 2.84(bs,2H), 2.05(s,3H), 1.60-1.40(m,13H), 1.14-1.12 (d, J = 8.0 Hz, 3H).

[0181] Process k [ka] A solution of A16 (15 g) in MeOH (90 mL) was treated with 5N HCl at room temperature within 15 minutes. l / IPA (45 mL) was added dropwise. After the addition, the mixture was stirred for 6 hours. IPA C (180 mL) was added dropwise to the above mixture at room temperature within 1 hour. The mixture was stirred for an additional 30 minutes before it was cooled to 0-5°C. After stirring for an additional 2 hours, the precipitate was collected by filtration. * 2mL) IPA C and dried under vacuum at 60° C. overnight to give the product as a white solid. 1 H NMR (400MHz, DMSO-d6)δ=9.37(br s,1H), 9.25 (br s,1H), 8.42(br s,3H), 4.26-4.17(m,1H), 3.72(ABq,J=9.1Hz, 2H), 3.50-3.41(m,1H), 3.2 8-3.18(m,1H), 3.18-3.09(m,1H), 2.99-2.74(m ,2H), 2.07-1.63(m,4H), 1.22(d,J=6.5Hz, 3H).

[0182] Process l [ka] A mixture of A17 (10 g) and Z17a (9.5 g) in DMAC (60 mL) was added to K CO (22.5 g) and H O (40 mL) were added at room temperature. The mixture was degassed with nitrogen. The mixture was cooled to room temperature and added with Me-THF (500 mL) and H2 The organic phase was separated and the aqueous phase was diluted with Me-THF (300 mL). * 2 The combined organic phase was extracted with brine (200 mL * 3) and concentrated under reduced pressure The residue was washed with IPA (60 mL) and H2O (20 mL) to remove most of the solvent. The mixture was diluted and stirred at 50°C for 1 hour, cooled to 5°C within 3 hours, and stirred at this temperature for 1 hour. The solid was collected by vacuum filtration and dried under reduced pressure to give the product as a yellow solid (12 g, 87.4%). 1 H NMR (400MHz, DMSO-d6)δ=7.64 (d,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6.1 3(s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1 H), 3.90-3.78(m,2H), 3.67(d,J=8.4Hz, 1H), 3. 49(d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1 Hz, 1H), 1.78-1.68(m,1H), 1.67-1.57(m,1H), 1 .56-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0183] Example 2 Formation of the succinate salt of the compound of formula I: This reaction is summarized by the following reaction scheme: [ka] A mixture of A18 (10 g) in MeOH (76 g) and H2O (24 g) was added at room temperature. Cinic acid (2.94 g) was added. The mixture was heated to 50° C. and stirred for 30 minutes to remove all solids. The resulting solution was added to IPA (190 mL) at 60-65°C. The mixture was stirred at 60°C for more than 5 hours, cooled to -15°C within 5 hours, and stirred at this temperature for more than 4 hours. The solid was collected by vacuum filtration and dried under reduced pressure to give the product as an off-white solid. (10.8 g, 82.8%) 1 H NMR (400 MHz, DMSO-d )δ=7.64(d,J=6.2Hz, 1H), 7.63(s,1H), 6.26(s, 2H), 6.16(s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4 .02(m,1H), 3.90-3.78(m,2H), 3.67(d,J=8.4Hz , 1H), 3.49(d,J=8.4Hz, 1H), 3.33(s,2H), 2.91( d,J=5.1Hz, 1H), 2.34(s,4H), 1.71-1.60(m,4H) , 1.13(d,J=6.5Hz,3H).

[0184] In a particular variation, the reaction follows the following reaction scheme, which is Optional milling for: [ka]

[0185] Example 3 Intermediate Z17a (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyridin-4-yl)thio Formation of chloropyrazine-2-amine), Variation 1: Compound Z17a can be prepared according to the following reaction scheme: [ka] Obtained according to.

[0186] In detail, the synthesis of compound Z17a was carried out as follows: Process a [ka] Under a nitrogen atmosphere, n-BuLi (2.5 M, 7.6 L) was dissolved in THF (15 L) at −78 °C. The resulting solution was added dropwise to a solution of 3-chloro-2-fluoropyridine (2 kg) in hexane. The resulting mixture was stirred for 1 h. Then, a solution of I2 (4.82 kg) in THF (6 L) was added. was added dropwise. After the addition, the reaction mixture was stirred for 30 minutes, and then saturated Na2SO3 ( 10 L) and warmed to 20-25°C. The phases were separated. The aqueous phase was diluted with EA (2 x 10 The combined organic phase was extracted with saturated Na2SO3 (2 x 8 L), brine (8 L). The organic phase was concentrated under reduced pressure and the residue was diluted with MeOH (4 L), filtered, dried and purified by filtration to give 3-chloro-2-fluoro-4-iodobenzoate. Dopyridine 1c (2.2 kg, 68% yield) was obtained.

[0187] Process b [ka] A solution of compound 1c (8 kg) in DMSO (48 L) was heated overnight at 80 °C with NH3 (Ga The reaction mixture was cooled to room temperature. The reaction mixture was added to water (140 L). The solid was collected, washed with water (25 L) and dried. As a result, Z17b (6.91 kg, yield 87%) was obtained. 1 H NMR (400 MHz, CD Cl3)δ=7.61(d,J=6.8Hz, 1H), 7.14(s,J=6.8Hz, 1H), 5.09(bs,2H).

[0188] Process c [ka] 2-Amino-6-chloro-pyrazine 1a (1 kg, 7.69 mo) in DCM (15 L) The solution of l) was heated to reflux and NBS (417 g) was added in portions over a period of 1 hour. The reaction mixture was cooled to room temperature and washed with water (3 L) and brine (3 L). The organic phase was evaporated and the residue was purified by column chromatography to give product Z. 17f (3-bromo-6-chloropyrazine-2-amine) (180 g, 11% yield) Got it.

[0189] Process d [ka] 3-Bromo-6-chloropyrazin-2-amine Z1 in 1,4-dioxane (40 L) A solution of 7f (6.0 kg, 28.78 mol) was added to Pd(OAc)2 under nitrogen at room temperature. (64.56g, 287.6mmol), Xantphos (333g, 575.6mmol ), and DIPEA (7.44 kg, 57.56 mol) were added. The mixture was then heated under nitrogen for another 30 minutes. After purging with nitrogen, methyl 3-mercaptopropanoate (3.81 kg, 31.70 mol ) was added, causing the orange mixture to darken. The mixture was heated to 90°C. LC showed complete conversion of the starting material. The mixture was cooled to about room temperature and then After aging for 30 minutes with stirring, the entire mixture was filtered. The solid was washed with EtOAc (3 x 15 L). The combined orange filtrate was concentrated. After evaporation to dryness, the solid residue was suspended in DCM (45 L). The mixture was heated to 35-40°C. The mixture was stirred for 1 hour until all solids were dissolved. Then, n-heptane (45 L) was added dropwise. After complete addition, the mixture was cooled to 15-20°C with stirring over 1 hour. The solid was collected by vacuum filtration and the solid was dissolved in cold 1:1 DCM / heptane (2 The solid was washed with water (5 L) and then with heptane (25 L) (PSC-2). The solid was dried over the weekend. This gave Z17d (5.32 kg, 75% yield). 1 H NMR (400 MHz, CDCl3)δ=7.83(s,1H), 4.88(bs,2H), 3.73(s,3H ), 3.47(t,J=9.2Hz, 2H), 2.79(t,J=9.2Hz, 2H).

[0190] Process e [ka] of Z17d (8.0 kg, assay 95%, 30.68 mol) in THF (70 L). The solution was added with EtONa (prepared from 776 g of Na and 13.6 L of EtOH) at room temperature. was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was then cooled to room temperature to form a wet yellow solid. The mixture was concentrated by rotary evaporation to 100°C and the residue was suspended in DCM (40 L). Stirred under N2 for 6 hours. Collect the solid by vacuum filtration, the filtrate becomes colorless. The cake was washed with DCM (approximately 15 L) until the solid was completely dissolved (PSC-2). Drying gave Z17c (6.93 kg, qNMR 72%, yield 88%). 1 HN MR(400MHz, D2O)δ=7.37(s,1H).

[0191] process f [ka] Z17c (6.95 kg, assay 72%, 27%) in 1,4-dioxane (72 L). A mixture of Xantphos (233 g, 411 mmol, 0.015 equiv.) , Pd2(dba)3 (186g, 206mmol, 0.0075 equivalent), Z17b(7 0.13 kg, 28.02 mol) and DIPEA (7.02 kg, 54.46 mol) The system was evacuated and purged with nitrogen gas three times. The mixture was stirred under N2 for 16 hours. The mixture was cooled to room temperature, water (50 L) was added, and the cake was filtered. The filtrate was extracted with EA (4 x 20 L). The organic phase was concentrated under reduced pressure. The crude product was then concentrated to give a crude product which was combined with the cake. DCM (60 L) was then added to the crude product. The mixture was added to the product and stirred at 25-30°C for 18 hours, and then filtered. The filter cake was The mixture was slurried with CH2Cl2 (30 L) for 16 hours and filtered. The mixture was slurried in CH2Cl2 (30 L) for 1 hour and filtered. The filter cake was then Drying under reduced pressure gave Z17a (3-((2-amino-3-chloropyridin-4-yl)thio) )-6-chloropyrazine-2-amine; 9.1 kg, 84%) was obtained as a pale yellow solid . 1 H NMR (400MHz, DMSO-d6)δ=7.89(s,1H), 7.7( d,J=7.6Hz, 1H), 7.18(bs,2H), 6.40(bs,2H), 5. 97(d,J=7.6Hz, 1H).

[0192] Example 4 Alternative Formation of Intermediate Z17a (also referred to herein as Y7a) Alternatively, and according to a preferred reaction method, a compound of formula Z17a can be reacted with the following reaction scheme: Room: [ka] In detail, the synthesis of the compound of formula Y7a=Z17a was carried out as follows: Found: Process a [ka] 2,3,5-trichloropyrazine (70.50g, 384.36mmol, 1eq) and and ammonia solution (25 wt%, 364.00 g, 400 mL, 2.68 mol, 6.1 4 equivalents) was added to a 1 L sealed reactor. The mixture was heated to 80°C and stirred for 24 hours. The reaction mixture was cooled to 30° C. and filtered to give a brown filter cake. The brown filter cake was dissolved in acetone (50 mL) and filtered. Petroleum ether (300 mL) was added. The suspension was stirred for 4 hours and filtered to give the crude product. The crude product was purified by a combined solution of petroleum ether and acetone (10 / 1, 200 mL). Slurrying in solvent and filtering afforded product Y7d (51.00 g, 307.91 mmol) , 80% yield) was obtained as a pale yellow solid. d6)δ=7.63(s,1H).

[0193] Process b [ka] In a 200 mL round-bottom flask, add NaS (10.816 g, 44 wt. % including water of crystallization, 60.978 mmol) and toluene (100 mL) were added. The mixture was heated to reflux. Water was removed in a Dean-Stark trap (approximately 5-6 mL of water was removed by distillation). After cooling, the mixture was concentrated to dryness.

[0194] Into the above round-bottom flask, Y7d (5.000 g, 30.489 mmol) and 2-methyl Loubutan-2-ol (50 mL) was added and the reaction was heated to reflux and stirred for 36 hours. After cooling to 25°C, the mixture was filtered. The filtrate was diluted with n-heptane (5V, 3 times, Y The mixture was then exchanged with THF (based on 7d) and concentrated to a final residue of 1V. The residue was charged with THF / n-heptane (5 mL) at 25° C. and stirred. The suspension was filtered and mL / 5 mL) to give a brown solid (6.200 g).

[0195] In a separate 200 mL round-bottom flask, add the brown solid (6,200 g) and 10% brine. (25mL), Me-THF (30mL) and n-Bu4NBr (9.829g, 30. The mixture was stirred at room temperature for 0.5 hours and the phases were separated. The organic phase Wash with 20% brine (25 mL) and dilute the solvent with isopropanol (5 mL). * 3 times, Y7d Y7c (27,000 g, 99.2% by HPLC area) was replaced with A solution of 1H NMR ( 400MHz, DMSO-d6)δ=6.88(s,1H), 2.97-2.92(m, 14H), 1.38-1.31(m,14H), 1.13-1.04(m,14H), 0 .73-0.69(t,21H).

[0196] Process c [ka] In a 25 mL round-bottom flask, add Y7c (4.7 g, 23.27 wt%, IP from step b) A solution, 2.723mmol, 1.0eq), Y7b (1.052g, 4.085mmo 1,10-phenanthroline (0.05 g, 0.272 mmol) and and water (8 mL) were added. The mixture was purged with nitrogen gas three times and CuI (0.026 g, 0.136 mmol) was added under a nitrogen atmosphere. The mixture was heated to 65°C and stirred for 3 hours. The reaction was completed by cooling to room temperature, filtering, and the filter cake was diluted with water (4 mL * 3) The filter cake was slurried in MTBE (6 mL) for 30 minutes and filtered. The filter cake was washed with MTBE (6 mL) and dried to give Z17a (565 mg, 72% yield). Y7a was obtained with a yield of 1.0.

[0197] Z17b is synthesized as described in Example 3, steps a and b.

[0198] Example 5 Alternative synthesis of intermediate Z17a: According to another preferred method, a compound of formula Z17a is reacted with a compound of formula Z17b according to the following reaction scheme: [ka] The reaction was carried out as follows: Process a Y7d was synthesized as described in Example 4, step a.

[0199] Process b [ka] In a three-necked round-bottom flask, Y7d (200 mg, 1.22 mmol, 1 equiv.), dioxane Xantphos (14 mL) was added. The solution was evacuated and purged with nitrogen gas three times. mg, 0.024 mmol, 0.02 eq), PdCl2(dppf) (8.9 mg, 0 0.012 mmol, 0.1 eq.), and DIPEA (0.32 g, 2.44 mmol, 2 0.0 equiv.) was added under a nitrogen atmosphere. The solution was heated to 85°C overnight. The reaction was cooled and The residue was purified by column chromatography (eluent: ethyl acetate / heptane = 1 Purification by HPLC / 1) gave Z17d (259 mg, 0.99 mmol, 81%). 1 H NMR (400MHz, CDCl3)δ=7.83(s,1H), 4.88(bs ,2H), 3.73(s,3H), 3.47(t,J=9.2Hz, 2H), 2.79( t, J = 9.2 Hz, 2 H).

[0200] The remaining steps were carried out as described in steps e and f of Example 4 to give Z17a. Z17b was synthesized as described in Example 3, steps a and b.

[0201] Example 6 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine, succinate (1:1) hemihydrate, modified (form) H A : Variation a) 50 ml of ethanol and 2.5 ml of water were added to 3.0 g of (3S,4S)-8-(6- Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl (amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine free salt group (obtained, for example, as A18, as described in Example 1) and 848.0 mg The mixture was heated to 50°C to give a clear solution. A solution was produced. The temperature was lowered to 15°C over a period of 3 hours. The solution was stirred overnight at 15°C. The precipitated solid was separated by suction filtration, and 50 ml of acetone was added to the suspension. A turbid liquid was produced. The suspension was stirred at 50°C for 3 hours. The solid was separated by suction filtration and The mixture was dried at room temperature under reduced pressure for 1 hour. The yield was about 60%.

[0202] The succinate has a melting point onset of 94.4°C and an associated enthalpy of 96 J / g. The succinate crystals appeared as a highly crystalline solid with broken, drusy, tabular structures. The particle aggregates were shown.

[0203] Variation b) 14.34 g of 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) Lysin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azas Pyro[4.5]decan-4-amine free form (e.g., as described in Example 1, A 18) and 4.053 g of succinic acid were added to 100 mL of 95% Equilibrated in EtOH. 5 mL of water was added to the system and heated to 70-75°C. 95 mL Pure EtOH was added and heated for an additional 30 minutes. Stirred overnight at 25°C. Filter the mixture. The product was dried under vacuum in an oven at room temperature. The yield was 87.5%. %.

[0204] The title succinate (1:1) obtained according to any one of variants a) and b) ) Hydrate salt modified H A It is highly crystalline. It can be used at room temperature and in a range of 10% RH to 50% RH. Succinate-modified HA maintains a constant water content above 1000 kJ / ml. It has high solubility in aqueous media. This indicates potentially good bioavailability.

[0205] The following XRPD data was obtained (table of 2θ values) (both variants):

[0206] [Table 1]

[0207] 1 H NMR (400MHz, DMSO-d6)δ 6.16(s,2H), 7.63 (d,J=5.8Hz, 2H), 6.27(s,2H), 5.86-5.60(m,1H ), 4.25-4.05(m,1H), 4.05-3.82(m,2H), 3.75(d ,J=8.7Hz, 1H), 3.56(d,J=8.7Hz, 1H), 3.24(ddd d,J=23.7, 13.4, 9.9, 3.3Hz, 2H), 3.09(d,J=5.0 Hz, 1H), 2.34(s,4H), 1.77-1.38(m,4H), 1.13(d ,J=6.4Hz,3H).

[0208] [Table 2]

[0209] Figure 1 shows the resulting XRPD diagram. Molar stoichiometry by NMR: 1:1.08 (base At 50°C / 75% RH, the succinate salt was used in all four experimental excipient mixtures. The acceptable degradation levels were shown.

[0210] Example 7 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine hydrochloride 50mg of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspirate 23.35 mg of 2,4-di[4.5]decan-4-amine in free form and 23.35 mg of hydrochloric acid were added over a period of 4 hours. The mixture was equilibrated in 1 mL of ACN at 50° C. After cooling to room temperature overnight, the mixture was filtered. This gives the hydrochloride salt.

[0211] The data suggested that solvate formation was likely. The following XRPD data Obtained (table of 2θ values).

[0212] [Table 3]

[0213] 1 H NMR(500MHz, DMSO-d6)δ 7.70-7.57(m,2H) , 6.26(s,2H), 6.17(s,2H), 5.74(d,J=5.4Hz, 1H ), 4.35(t,J=5.0Hz, 1H), 4.28-4.13(m,2H), 4.1 1(d,J=13.8Hz, 1H), 3.90(d,J=9.0Hz, 1H), 3.67 (d, J=8.9Hz, 1H), 3.43(td, J=7.0, 4.9Hz, 1H), 1 .84-1.48(m,4H), 1.23(d,J=6.6Hz, 3H).

[0214] [Table 4]

[0215] FIG. 2 shows the resulting XRPD diagram.

[0216] Example 8 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine mesylate 50mg of 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro [4.5] Decane-4-amine free form and 11.62 mg of methylsulfonic acid were added to 50 The mixture was equilibrated in 1 mL of THF at 10°C. After cooling to room temperature overnight, the mixture was filtered. This gives the mesylate salt.

[0217] The data suggested that solvate formation was likely. The following XRPD data Obtained (table of 2θ values).

[0218] [Table 5]

[0219] 1 H NMR (500MHz, DMSO-d6)δ 7.88(s,3H), 7.74 -7.61(m,2H), 6.31(s,2H), 5.96(d,J=6.4Hz, 1H ), 4.34-4.06(m,4H), 3.88(d,J=9.0Hz, 2H), 3.4 7-3.31(m,3H), 2.31(s,6H), 1.85-1.40(m,4H), 1.22 (d, J = 6.5 Hz, 3H).

[0220] [Table 6]

[0221] FIG. 3 shows the resulting XRPD diagram.

[0222] Example 9 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine, fumarate 50mg of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspirate B[4.5]decan-4-amine in free form and 13.89 mg of fumaric acid were mixed at 50°C. The mixture was equilibrated in 1 mL of EtOH, cooled to room temperature overnight, and filtered. , the fumarate salt is obtained.

[0223] The following XRPD data was obtained (table of 2θ values):

[0224] [Table 7]

[0225] 1 H NMR(500MHz, DMSO-d6)δ 7.63(d,J=6.4Hz, 2H), 6.52(s,2H), 6.26(s,2H), 6.14(s,2H), 5.7 4(d,J=5.3Hz, 1H), 4.20-4.02(m,1H), 3.97(dd, J=19.6, 14.4Hz, 2H), 3.76(d,J=8.6Hz, 1H), 3.5 6(d,J=8.7Hz, 1H), 3.32-3.16(m,3H), 3.11(d,J =5.1Hz, 1H), 1.82-1.37(m,4H), 1.14(d,J=6.5H) z, 3H).

[0226] [Table 8]

[0227] FIG. 4 shows the resulting XRPD diagram.

[0228] Example 10 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine adipate (1:1), Modification A 30 ml of acetonitrile was dissolved in 3.0 g of (3S,4S)-8-(6-amino-5-( (2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl 1.0 g of adipine and 1.0 g of benzoyl-2-oxa-8-azaspiro[4.5]decane-4-amine The resulting suspension was heated to 50°C for 3 hours. The mixture was heated and then cooled to 15° C. for 3 hours. The suspension was left stirring overnight at 15° C. The solid was separated by suction filtration and dried at 40°C under reduced pressure for 12 hours. The yield of the adipate-modified A obtained was approximately 80%.

[0229] Adipate has a melting point onset of 145.3°C and an associated enthalpy of 90 J / g. The adipate crystals appeared as a highly crystalline solid. The adipate crystals showed aggregates of tabular grains.

[0230] Molar stoichiometry by NMR: 1:1.02 (base:adipic acid). XRPD data as follows: The data was obtained (table of 2θ values).

[0231] [Table 9]

[0232] 1 H NMR (400MHz, DMSO-d6)δ 7.63(d,J=5.3Hz, 2H), 6.27(s,3H), 6.14(s,2H), 5.74(d,J=5.3Hz , 1H), 4.19-4.00(m,1H), 3.98-3.77(m,2H), 3.6 8(d,J=8.5Hz, 1H), 3.49(d,J=8.5Hz, 1H), 3.33( dddd,J=31.4, 13.1, 9.3, 3.4Hz, 2H), 2.93(d,J= 5.1Hz, 1H), 2.28-2.09(m, 4H), 1.80-1.56(m, 2H) ), 1.57-1.37(m,6H), 1.09(d,J=6.4Hz, 3H).

[0233] [Table 10]

[0234] Figure 5 shows the resulting XRPD diagram. Adipate is a soluble form of mannitol, Ac-di-So A mixture of pharmaceutical ingredients containing cellulose and microcrystalline cellulose showed strong degradation.

[0235] Example 11 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine, succinate (1:1), anhydrous form, modified A 2.0 g of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspirate 1.13 g of 4.5-decan-4-amine free form and succinic acid were added to EasyMax After adding the mixture to the reactor, 40 mL of ethanol was added, and the resulting mixture was heated at 25°C for 3 days. The mixture was filtered, the solid phase was washed with 40 mL of ethanol and dried at ambient temperature. This gave the monosuccinate, anhydrous form, Modification A.

[0236] The following XRPD data was obtained (table of 2θ values):

[0237] [Table 11]

[0238] 1 H NMR(400MHz, DMSO-d6)δ 7.73-7.53(m,2H) , 6.27(s,2H), 6.16(s,2H), 5.73(d,J=5.4Hz, 1H ), 4.26-4.03(m,1H), 4.04-3.87(m,2H), 3.75(d ,J=8.7Hz, 1H), 3.56(d,J=8.7Hz, 1H), 3.23(ddd d,J=23.6, 13.3, 9.9, 3.3Hz, 2H), 3.10(d,J=5.0 Hz, 1H), 2.35(s,5H), 1.72-1.40(m,4H), 1.13(d ,J=6.4Hz,3H).

[0239] [Table 12]

[0240] FIG. 6 shows the resulting XRPD diagram.

[0241] Example 12 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine, succinate (2:1), hydrate, modified H A 2g of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine -4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[ 4.5]Decan-4-amine monosuccinate, hydrate, modified H A into a suitable flask 20 mL of a mixture of acetonitrile / water (80:20, vol / vol) was added to the flask. The resulting suspension was stirred overnight. The mixture was filtered and allowed to stand at ambient temperature until a solid phase formed. This resulted in the formation of hemisuccinate, hydrate, modified H A was obtained.

[0242] The following XRPD data was obtained (table of 2θ values):

[0243] [Table 13]

[0244] 1 H NMR(400MHz, DMSO-d6)δ 7.73-7.50(m,2H) , 6.26(s,2H), 6.14(s,2H), 5.74(d,J=5.4Hz, 1H ), 4.17-4.02(m,1H), 3.91(t,J=13.0Hz, 2H), 3. 72(d,J=8.6Hz, 1H), 3.53(d,J=8.6Hz, 2H), 3.01 (d,J=5.1Hz, 1H), 2.33(s,2H), 1.85-1.40(m,4H ), 1.11(d,J=6.4Hz, 3H).

[0245] [Table 14]

[0246] Figure 7 shows the resulting XRPD.

[0247] Example 13 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine free base modified A 12g of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro [4.5]Decan-4-amine was added to 150 mL of IPA. The mixture was heated at 70°C. The mixture was stirred for 30 minutes to dissolve all of the solids, cooled to 25°C over 2 hours, and then The solid was collected by vacuum filtration and dried under reduced pressure to give the free form modified A (10.4g, 86.7%)

[0248] The free form showed strong degradation in excipient mixtures containing HPMC.

[0249] The following XRPD data was obtained (table of 2θ values):

[0250] [Table 15]

[0251] 1 H NMR(400MHz, DMSO-d6)δ 7.72-7.54(m,2H) , 6.25(s,2H), 6.12(s,2H), 5.74(d,J=5.3Hz, 1H ), 4.06(qd, J=6.4, 5.1Hz, 1H), 3.83(tt,J=13.2 , 5.5Hz, 2H), 3.66(d,J=8.4Hz, 1H), 3.48(d,J=8 .5Hz, 1H), 3.44-3.22(m,3H), 2.90(d,J=5.1Hz, 1H), 1.72(ddd,J=13.2, 9.3, 3.8Hz, 1H), 1.62(d dd,J=13.1, 9.0, 4.0Hz, 1H), 1.48(ddt,J=20.1, 13.2, 3.5Hz, 2H), 1.08(d,J=6.4Hz, 3H).

[0252] [Table 16]

[0253] Figure 9 shows the resulting XRPD.

[0254] Example 14 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine, succinate (2:1), anhydride, modified A 1.0 g of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) (4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspirate B[4.5]decane-4-amine monosuccinate, hydrate, modified HA was added to 20 mL of The mixture was placed in a glass vial and 5 mL of methanol was added. The resulting mixture was left for 1 week. The mixture was stirred at 50°C. The mixture was filtered and dried at ambient temperature until it became a solid phase. This gives the hemisuccinate, anhydride, and modified A.

[0255] The following XRPD data was obtained (table of 2θ values):

[0256] [Table 17]

[0257] 1 H NMR(400MHz, DMSO-d6)δ 7.77-7.51(m,2H) , 6.26(s,2H), 6.14(s,2H), 5.74(d,J=5.4Hz, 1H ), 4.22-3.99(m,1H), 3.91(t,J=13.7Hz, 2H), 3. 72(d,J=8.6Hz, 1H), 3.54(d,J=8.6Hz, 2H), 3.02 (d,J=5.1Hz, 1H), 2.34(s,3H), 1.86-1.39(m,4H ), 1.11(d,J=6.4Hz, 3H).

[0258] [Table 18]

[0259] Figure 8 shows the resulting XRPD.

[0260] Example 15 (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] Decane-4-amine succinate (2:1), hydrate, modified H B : The title compound is a succinate (2:1) modified H A obtained during DVS.

[0261] [Table 19]

[0262] Example 16 Comparison of various forms of Examples 6-14: The anhydrous form is prepared by dissolving the modified H in an aqueous organic solvent mixture with very little water (1-2%). A Rapidly succinate hemihydrate (modified H A ) (Example 6) in its anhydrous form (Modification A) was chosen to prevent risk of morphological changes during stable storage or tableting. Furthermore, modified H A was selected over the hemisuccinate form because They are highly hygroscopic and A This is because it exhibited a higher degree of polymorphism.

[0263] Succinate-modified H of Example 6 A is maintained at room temperature at a constant RH of 10% to 50%. The succinate-modified HA of Example 6 exhibits high solubility in aqueous media. This indicates potentially good bioavailability.

[0264] [Table 20]

[0265] FaSSIF = fasting artificial intestinal fluid (V2: sodium taurocholate 3 mM, lecithin 0 0.2mM, sodium chloride 68.6mM, maleic acid 19.1mM, sodium hydroxide 1 01mM, pancreatin 10.0mg / l).

[0266] FeSSIF V2 = fed artificial intestinal fluid (V2: 10 mM sodium taurocholate, 2.0 mM lecithin, 0.8 mM sodium oleate, 5.0 mM monoolein Acid glycerol, 125.5 mM sodium chloride, 81.7 mM sodium hydroxide, 55.0 mM maleic acid, pancreatin 40.0 mg / l).

[0267] SGF = artificial gastric fluid (sodium chloride 2 g / l, triton X-100 1 g / l, 100ml / l of HCl 0.1M.

[0268] At 50°C / 75% RH, succinate form H A is mixed with the following four excipients: When tested, all four experimental excipient mixtures showed acceptable levels of degradation (free form , showed strong degradation in the mixture containing HPMC, and adipate showed strong degradation in the mixture containing mannitol, Ac- Strong degradation is observed in mixtures containing di-Sol and microcrystalline cellulose): Mixture 1: Gelatin powder Mixture 2: HPMC Mixture 3: MCC PH101 (45% by weight); Lactose monohydrate (44% by weight), P VP K30 (4 wt%), Aerosil (0.5 wt%), Mg stearate (1. 5% by weight), and then 20% by weight of water was added to the mixture. Blend 4: Mannitol DC (68.7% by weight), MCC PH102 (26% by weight), Ac-di-Sol (4% by weight), Aerosil (0.3% by weight), magnesium stearate (1% by weight).

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt, acid co-crystal, hydrate or other solvate thereof A method for manufacturing an article, comprising: The reaction scheme below: 【Chemistry 1】 wherein A is the anion of an acid, LG is a leaving group, and the compound of formula II is electrically unsaturated. wherein n and m are integers selected from 1, 2, and 3, such that a compound of formula II with a compound of formula III.

2. The reaction scheme below: 【Chemistry 2】 (In the formula, R １ is a protecting group, HY is a chiral acid, A is an anion of the acid, n and m are selected from 1, 2, and 3, such that the compound of formula II is electrically uncharged. wherein the compound of formula IV is converted into a compound of formula H ｎ A to form a compound of formula I 10. The method of claim 1, further comprising obtaining a compound of formula I.

3. The reaction scheme below: 【Transformation 3】 (In the formula, R １ is a protecting group and HY is a chiral acid), further comprising reacting the salt with a chiral acid of formula HY to obtain a compound of formula IV.

3. The method according to claim 1 or 2.

4. The reaction scheme below: 【Chemistry 4】 (In the formula, R １ is a protecting group, and R ２ is alkyl), to prepare a compound of formula VI 4. The method of claim 1, further comprising reacting to obtain a compound of formula V How to do it.

5. The reaction scheme below: 【Transformation 5】 (In the formula, R １ is a protecting group, and R ２ is alkyl), and thus a compound of formula VII to obtain a compound of formula VI. The method described.

6. The reaction scheme below: 【Transformation 6】 (In the formula, R １ is a protecting group, and R ２ is alkyl), the compound of formula VIII and reacting the compound of formula VII with a compound of formula IX to obtain a compound of formula VII.

6. The method according to any one of 1 to 5.

7. The reaction scheme below: 【Transformation 7】 (In the formula, R １ is a protecting group) to give a compound of formula VIII The method of any one of claims 1 to 6, further comprising obtaining the compound.

8. The reaction scheme below: 【Transformation 8】 (In the formula, R １ is a protecting group, and Pr １ O is a leaving group, and Pr ２ is a substituted silyl protecting group cyclizing the compound of formula XI according to the method of formula (I) to obtain a compound of formula X. The method according to any one of claims 1 to 7.

9. The reaction scheme below: 【Chemistry 9】 (In the formula, R １ is a protecting group, and Pr １ O is a leaving group, and Pr ２ is a substituted silyl protecting group ) by reacting a compound of formula XII with a compound of formula Pr １ H to form a compound of formula XI The method of any one of claims 1 to 8, further comprising obtaining a mixture.

10. The reaction scheme below: 【Chemistry 10】 (In the formula, R １ is a protecting group, and Ra is unsubstituted or substituted alkyl or unsubstituted or is a substituted aryl group, Pr ２ is a substituted silyl protecting group), 10. The method of claim 1, further comprising reducing the compound to obtain a compound of formula XII.

1. The method according to claim 1.

11. The reaction scheme below: 【Chemistry 11】 (In the formula, R １ is a protecting group, and Ra is unsubstituted or substituted alkyl or unsubstituted or is a substituted aryl group, Pr ２ is a substituted silyl protecting group), to form a compound of formula XIV and reacting the compound of formula XV with a compound of formula XIII to obtain a compound of formula XIII. The method according to any one of claims 1 to 10.

12. The reaction scheme below: 【Chemistry 12】 (Wherein, Pr ２ is a substituted silyl protecting group, and R ３ is an alkyl group, and R ４ is an alkyl group and reducing the compound of formula XVI to obtain a compound of formula XIV according to the method of The method of any one of claims 1 to 11, further comprising:

13. The reaction scheme below: 【Chemistry 13】 (Wherein, Pr ２ is a substituted silyl protecting group, and R ３ is an alkyl group, and R ４ is an alkyl group and R ５ is an unsubstituted or substituted alkyl group or an unsubstituted or substituted aryl group ester compounds of formula XVII are converted into ester compounds of formula R ４ ONHR ３ reacted with the compound to obtain a compound of formula XVI. How to do it.

14. The reaction scheme below: 【Chemistry 14】 (Wherein, Pr ２ is a substituted silyl protecting group, HAL is halo, and R ５ But non-substituted or is a substituted alkyl group or an unsubstituted or substituted aryl group, The compound of formula I is ２ and protecting with a compound of formula XVII to give a compound of formula XVII. The method according to any one of claims 1 to 13, further comprising:

15. The reaction scheme below: 【Chemistry 15】 According to the formula H ｒ B, in salt or free base form, of the formula I is a compound of formula I ＊ to an acid addition salt of

16. The compound of formula XVIII is reacted with a halogenating agent: 【Chemistry 16】 wherein LG is a leaving group to give a compound of formula XIX: 【Chemistry 17】 wherein LG is a leaving group and Hal is a halogen, which is then converted to a compound of formula XX Mercapto compounds of R ６ O-C(=O)-CH ２ -CH ２ -SH (XX) (In the formula, R ６ is unsubstituted or substituted alkyl or unsubstituted or substituted aryl and replacing the compound of formula XXI with [Chemistry 18] wherein LG is a leaving group and R ６ is unsubstituted or substituted alkyl or unsubstituted or and then reacting said compound of formula XXI with an alkali metal aryl. alkoxylate to give a compound of formula XXII 【Chemistry 19】 wherein Mt is an alkali metal, and then reacting the compound of formula XXII with a compound of formula XX Compound III 【Chemistry 20】 to produce the compound of formula III 【Chemistry 21】 and obtaining a compound of formula III according to claim 1, wherein LG is a leaving group. Manufacturing method.

17. Compound of Formula XXIII 【Chemistry 22】 in the presence of a strong base, 【Chemistry 23】 with iodine; and obtaining a compound of formula XXV 【Chemistry 24】 with ammonia to obtain a compound of formula XXIII.

18. Formula I ＊ Compound of: 【Chemistry 25】 (In the formula, H ｒ B is a mixture of succinic acid, hydrochloric acid, methylsulfonic acid, fumaric acid, and adipic acid an acid selected from the group consisting of: and at least one pharmaceutically acceptable carrier.

19. 19. The compound of claim 18 in crystalline form.

20. (3S,4S)-8-(6-amino-5-((2-amino-3-chloro- (isopropylpyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-a Zaspiro[4.5]decan-4-amine monosuccinate free base.

21. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ]Decan-4-amine succinate (1:1) hydrate form H Ａ 19. The compound according to claim 18, compound.

22. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ] The compound of claim 18, which is decan-4-amine hydrochloride.

23. 23. The compound of claim 22 in crystalline form.

24. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ] The compound of claim 18, which is decan-4-amine mesylate.

25. 25. The compound of claim 24 in crystalline form.

26. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 20. The compound of claim 18, wherein the compound is decane-4-amine fumarate.

27. 19. The compound of claim 18 in crystalline form.

28. (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4- yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5 ] The compound of claim 18, which is decan-4-amine adipate.

29. 29. The compound of claim 28 in crystalline form.

30. (3S,4S)-8-(6-amino-5-((2-amino-3-chloro)- (isopropylpyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-a 19. The compound according to claim 18, which is zaspiro[4.5]decan-4-amine, succinate (1:1). The compound described.

31. 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] The compound of claim 18, which is decan-4-amine, succinate (2:1) hydrate. 。

32. 3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine-4-yl) (I)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] The compound of claim 18, which is decan-4-amine, succinate (2:1) anhydrous. 。

33. Formula I according to any one of claims 18 to 32 ＊ A pharmaceutical composition comprising the compound of formula (I).

34. Formula I ＊ The compound (3S,4S)-8-(6-amino-5-((2-amino-3 -chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5]decane-4-amine succinate (1:1) hydrate form H Ａ Yes The composition of claim 33.

35. A method of treatment comprising administering to a patient of formula I according to any one of claims 18 to 32. ＊ The compound and preventing a disease or disorder mediated by the activity of SHP2 in a patient in need of such treatment. The method comprises administering to a subject a therapeutically effective amount of a compound of formula (I) or (II) in an amount effective for therapeutic or therapeutic treatment.

36. The disease or disorder mediated by the activity of SHP2 is Noonan syndrome, Leopard syndrome, syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, ectopic pregnancy syndrome, Cancer of the esophagus, lung cancer, colon cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, gastric cancer, undifferentiated large cell carcinoma 36. The method of claim 35, wherein the tumor is selected from lymphoma and glioblastoma.

37. 33. The method according to any one of claims 18 to 32, for simultaneous, sequential or separate administration. Formula I ＊ and one or more other pharmacologically active compounds, particularly antiproliferative agents.

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