EA042733B1 - SYNTHESIS OF N-(HETEROARYL)PYRROLO[3,2-d]PYRIMIDINE-2-AMINES - Google Patents

Description

Cross-reference to related applications

This application claims the priority of Provisional Application US 62/357,797, which was filed July 1, 2016. This application is incorporated herein by reference in its entirety and for all purposes.

Field of invention

This invention relates to the field of synthesizing pyrimidine-based compounds useful in the treatment of disorders characterized by abnormal cell proliferation, including, but not limited to, tumors and various types of cancer.

State of the art

US Patents #8,822,683; 8598197; 8,598,186, 8,691,830, 8,691,830, 8,829,102, 8,822,683, 9,102,682, 9,499,564, 9,481,591 and 9,260,442, filed by Tavares and Strum and owned by G1 Therapeutics describe a class of N-pyrrolo-visimyrimidine inhibitors including formula inhibitors (with variables as defined in these patents):

US Pat. Nos. 9,464,092, 9,487,530, and 9,527,857 also owned by G1 Therapeutics describe the use of the aforementioned pyrimidine-based agents in the treatment of cancer.

These patents provide a general synthesis of compounds which is based on the reaction of the coupling of a condensed chloropyrimidine with a heteroarylamine to form a central disubstituted amine. Such coupling reactions are sometimes referred to as Buchwald coupling (see WO 156, paragraph 127; reference WO 2010/020675). A fused chloropyrimidine lactam, for example 2chlorospirocyclopyrrolo[2,3-d]pyrimidin-one, such as intermediate K as shown below, can be prepared by dehydration of the corresponding carboxylic acid. The described method for preparing intermediate 1K requires a reaction in seven steps.

(intermediate 1K; page 60, paragraph 215 of WO '156).

WO 2013/148748 (USSN 61/617,657), entitled Lactam kinase inhibitors, filed by Tavares and also owned by G1 Therapeutics, similarly describes the synthesis of N(heteroaryl)npyrrolo[3,2-d]pyrimidine-2-amines via a condensed chloropyrimidine with heteroarylamine to form a central disubstituted amine.

WO 2013/163239 (USSN 61/638,491) Synthesis of lactams describes a process for the synthesis of this class of compounds, with the modification that, in the lactam preparation step, a carboxylic acid may be cyclized with a protected amine in the presence of a strong acid and a dehydrating agent, which may be present together in one fragment in the form of an anhydride of a strong acid. The intended improvement is that cyclization can occur without loss of the protecting group on the amine prior to cyclization. A typical leaving group is tBOC (tert-butoxycarbonyl). The application discloses (page 2 of WO 2013/163239) that a strong acid is, for example, trifluoroacetic anhydride, tribromoacetic anhydride, trichloroacetic anhydride or mixed anhydrides. An additional N-protecting group removal step may be required. The dehydrating agent may be a carbodiimide-based compound such as DCC (N,N-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DIC (N,N-diisopropylcarbodiimide). DCC and DIC refer to to the same class of carbodiimide reagents DIC is sometimes considered better because at room temperature it is a liquid, which facilitates reactions.

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WO 2015/061407 filed by Tavares and licensed to G1 Therapeutics also describes the synthesis of these compounds by coupling a fused chloropyrimidine to a heteroarylamine to form a central diamine. WO 407 deals with the lactam preparation step and specifically describes that the fused lactams of these compounds can be obtained by treating the carboxylic acid with an acid and a dehydrating agent such that the leaving group on the amine is not removed during the amide ring closing step.

Other publications that describe compounds of this general class include the following. WO 2014/144326 filed by Strum et al. and owned by G1 Therapeutics describes compounds and methods for protecting normal cells during chemotherapy with pyrimidine-based CDK4/6 inhibitors. WO 2014/144596, filed by Strum et al. and owned by G1 Therapeutics, describes compounds and methods for protecting hematopoietic stem and progenitor cells from ionizing radiation using pyrimidine-based CDK4/6 inhibitors. WO 2014/144847 filed by Strum et al. and owned by G1 Therapeutics describes HSPC-sparing treatment of abnormal cell proliferation using pyrimidine-based CDK4/6 inhibitors. WO 2014/144740 filed by Strum et al. and owned by G1 Therapeutics describes highly potent pyrimidine-based antineoplastic and antiproliferative inhibitors of CDK 4/6. WO 2015/161285 filed by Strum et al. and owned by G1 Therapeutics describes tricyclic pyrimidine CDK inhibitors for use in radioprotection. WO 2015/161287 filed by Strum et al. and owned by G1 Therapeutics describes similar pyrimidine-based tricyclic CDK inhibitors for cell protection during chemotherapy. WO 2015/161283 filed by Strum et al. and owned by G1 Therapeutics describes similar tricyclic pyrimidine CDK inhibitors for use in HSPC-sparing treatments for RB-positive abnormal cell proliferation. WO 2015/161288 filed by Strum et al. and owned by G1 Therapeutics describes similar tricyclic pyrimidine based CDK inhibitors for use as antitumor and antiproliferative agents. WO 2016/040858 filed by Strum et al. and owned by G1 Therapeutics describes the use of pyrimidine-based CDK4/6 inhibitor combinations with other anticancer agents. WO 2016/040848 filed by Strum et al. and owned by G1 Therapeutics describes compounds and methods for the treatment of certain Rb-negative cancers with CDK4/6 inhibitors and topoisomerase inhibitors.

Other biologically active condensed spirolactams and their synthesis are described, for example, in the following publications. Griffith, D.A., et al. (2013). Spirolactam-Based Acetyl-CoA Carboxylase Inhibitors: Toward Improved Metabolic Stability of a Chromanone Lead Structure. Journal of Medicinal Chemistry 56 (17): 7110-7119 describes metabolically stable spirolactams in which the lactam is on a fused ring, designed to inhibit acetyl-CoA carboxylase. WO 2013/169574 filed by Bell et al. describes aliphatic spirolactams as CGRP receptor antagonists, the lactam being on the spiro ring. WO 2007/061677 filed by Bell et al. describes arylspirolactams as CGRP receptor antagonists, the lactam being on the spiro ring. WO 2008/073251 filed by Bell et al. describes conformationally constrained spirolactam compounds relative to each other, the lactam being on the spiro ring, as CGRP receptor antagonists. WO 2006/031606 filed by Bell et al. describes carboxamide-spirolactam compounds wherein the spirolactam is on the spiro ring as CGRP receptor antagonists. WO 2006/031610, WO 2006/031491 and WO 2006/029153 filed by Bell et al. describe anilide spirolactam compounds wherein the spirolactam is on the spiro ring; WO 2008/109464 filed by Bhunai et al. describes spirolactam compounds in which the lactam is on a spiro ring which can be further condensed.

Given the therapeutic activity of the selected N-(heteroaryl)pyrrolo[3,2-d]pyrimidine-2vmins, it would be useful to have additional methods for their preparation. It would also be useful to have new intermediates that could be used to prepare this class of compounds.

The essence of the invention

It has been found that 2'-(heteroaryl)lactam-pyrrolo[3,2-d]pyrimidines are predominantly prepared by coupling an alkylsulfone- or alkylsulfoxide-substituted fused pyrimidine to a heteroarylamine to form the central disubstituted amine in yields greater than about 50%. In one embodiment of the invention, the reaction is carried out at a temperature equal to or lower than about 20, 18, 16, 14, 12, or 10°C. In another embodiment, the ratio of amine to sulfone is at least about 2:1. In another embodiment, the ratio of amine to sulfone is at least about 3:1. The use of an alkylsulfone- or alkylsulfoxide-substituted condensed pyrimidine instead of a chlorine-substituted condensed pyrimidine increases the yield of the diamine product obtained in the coupling reaction.

In another aspect of the present invention, the novel process is for the preparation of 2'(alkylsulfonyl or alkylsulfinyl)pyrrolo[2,3-d]pyrimidines which can be used in a coupling reaction with a heteroaryl amine. As one illustrative example, the present invention relates to 2'-(alkylsulfonyl or alkylsulfinyl)pyrrole[2,3-d]pyrimidine, which has the following structure.

- 2 042733

According to the invention, 2'-(alkylsulfonyl or alkylsulfinyl)pyrrolo[2,3-b]pyrimidine is prepared using an ester or an aldehyde as a starting material. For example, the ester may be an alkyl 4-chloro-2-(alkylthio)pyrimidine-5-carboxylate such as ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate. The aldehyde may be 4-chloro-2(alkylthio)pyrimidine-5-carbaldehyde such as 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde. The reaction from the ester to the key intermediate 2'-(alkylsulfonyl or alkylsulfinyl)pyrrole[2,3b]pyrimidine typically takes seven steps (some of which can be done without isolating the compound), each of which typically provides over 50% yield. Each stage is described in detail below.

The process for preparing 2'-(alkylsulfonyl or alkylsulfinyl)pyrrolo[2,3-b]pyrimidine is an easy and efficient route which consists of seven steps with only five isolations, all of which are carried out by crystallization. No column chromatography is required, allowing the process to be scaled up for large production batches. Additionally, the process conditions are such that most of the palladium is successfully removed after step 5. The observed level of residual palladium is below residual ppm. threshold for heavy metal content.

In addition, the present invention includes new intermediates of formula II, which can be used in the process for the preparation of lactam-pyrrolo[2,3-b]pyrimidines of formula IV. In another aspect of the present invention, the synthesis of compounds of formula I, formula II, formula III and formula IV is provided. In one non-limiting embodiment, the compounds of formula I, formula II and formula III are synthetic precursors of the compound of formula IV.

where ---- ^z= represents the presence or absence of a double bond;

O

VV is a carbocycle of 3 to 8 carbons (independently including 3, 4, 5, 6 and 7 _i „A „ „ _i carbon atoms, and in particular where W is cyclohexyl) spiro-linked to a lactam ring, wherein the spirocycle is optionally substituted;

R ¹ is selected from: alkyl, aryl, haloalkyl and arylalkyl;

R ² and R ³ are independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;

R ⁴ is selected from: hydrogen, silyl, haloalkyl, -C(O)alkyl, -S(O) ₂ -alkyl, -S(O) ₂ -haloalkyl, -S(O) ₂ -aryl, and -S(O) _2- arylalkyl; and

R ⁵ is selected from: hydrogen, halogen, -N(alkyl)(alkoxy), -NCH ₃ OMe, alkoxy, aryloxy, -OCH ₂ -aryl, -OC(O)alkyl, -OC(O)aryl and -OC( O) arylalkyl.

In one embodiment, the heteroarylamine is dissolved in a polar solvent and the alkyl sulfone or alkyl sulfoxide is added in portions at temperatures equal to or below about 20, 18, 16, 14, 12, or 10° C., wherein the ratio of amine to sulfone is at least about 2: 1 and a base to sulfone ratio of at least 2:1 is used to prepare the central disubstituted amine in yields greater than about 50%.

In another embodiment, the heteroarylamine is dissolved in a polar solvent and the alkyl sulfone or alkyl sulfoxide is added in portions, with an amine to sulfone ratio of at least about 2:1 and a base to sulfone ratio of at least 2:1 being used to form the central disubstituted amine in yields greater than about 50%.

In one embodiment, the heteroarylamine is dissolved in a polar solvent and the alkyl sulfone or alkyl sulfoxide is added in portions at temperatures equal to or below about 20, 18,

- 3 042733

16, 14, 12, or 10° C., where an amine to sulfone ratio of at least about 3:1 and a base to sulfone ratio of at least 2:1 are used to produce the central disubstituted amine in yields greater than about 50%.

In another embodiment, the heteroarylamine is dissolved in a polar solvent and the alkyl sulfone or alkyl sulfoxide is added in portions at temperatures equal to or below about 20, 18, 16, 14, 12, or 10° C., where an amine to sulfone ratio of at least about 3 :1, and a base to sulfone ratio of at least 3:1. After the addition was complete, the reaction mixture was quenched with ammonium chloride to recover the central disubstituted amine in yields greater than about 50%.

In one embodiment, after completion of the reaction, the reaction mixture is quenched with ammonium chloride to recover the central disubstituted amine in yields greater than about 50%.

In one embodiment, the base is LiHMDS.

In one non-limiting embodiment, 2'-(alkylsulfonyl or alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine is prepared from the starting ester, which includes the following steps:

(i) nucleophilic attack of the compound of formula V with an aminolactam to form alkyl-2(alkylthio)-4-(lactam)pyrimidine-5-carboxylate;

(ii) optional protection of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate;

(iii) cyclization of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate to give 5'hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine;

(iv) converting the hydroxyl group of 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine into a leaving group;

(v) dehydration of the compound obtained in (iv) to obtain 2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine;

(vi) optional deprotection of the 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine; and then (vii) optional oxidation of the mercapto group of 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

In an alternative embodiment, the oxidation, protection or deprotection mentioned above are in a different order or removed as far as the reagents and substrates used allow. For example, if the amino lactam in step (i) above is already protected, then step (ii) is skipped.

In another embodiment, step (vi) and step (vii) are reversed. In one non-limiting embodiment, a method for synthesizing a compound of formula IV includes the following steps:

(i) nucleophilic attack of a compound of formula V with a compound of formula I to obtain a compound of formula II;

(ii) optional protection of the compound of formula II;

(iii) cyclization of a compound of formula II to give a compound of formula III, where R ⁴ is H;

(iv) replacing the hydrogen R ⁴ with a group other than hydrogen, which facilitates subsequent dehydration; (v) dehydration of the compound of formula III to obtain a compound of formula IV;

(vi) optional deprotection of the compound of formula IV; and then (vii) optionally oxidizing the mercapto group of formula IV to a sulfone. In another embodiment, a method for synthesizing a compound of formula IV comprises the steps of:

(i) cyclization of a compound of formula II to give a compound of formula III, where R ⁴ is H;

(ii) replacing the hydrogen R ⁴ with a group other than hydrogen, which facilitates subsequent dehydration;

(iii) dehydration of the compound of formula III to obtain a compound of formula IV;

(iv) optional deprotection of the compound of formula IV; and (v) optionally oxidizing the mercapto group of formula IV to a sulfone.

In another embodiment, a method for synthesizing a compound of formula IV comprises the steps of:

(i) dehydration of the compound of formula III to obtain a compound of formula IV;

(ii) optional deprotection of the compound of formula IV; and then (iii) optionally oxidizing the mercapto group of formula IV to a sulfone.

In one non-limiting embodiment of the invention, a method for synthesizing 2'(alkylsulfonyl or alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine from an aldehyde starting material includes the following steps:

(i) nucleophilic attack of the compound of formula VI with an aminolactam to form an alkyl-2-

- 4 042733 (alkylthio)-4-(lactam)pyrimidine-5-carboxylate;

(ii) optional protection of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate;

(iii) cyclization of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate to give 2'(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine;

(iv) optionally deprotecting the 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine; and then (v) optionally oxidizing the mercapto group of the 2'-(alkylthio)lactam-pyrrolo[2,3-0]pyrimidine.

In an alternative embodiment, the oxidation, protection or deprotection mentioned above is rearranged or removed as far as the reagents and substrates that are used allow. For example, if the amino lactam in step (i) above is already protected, then step (ii) is skipped.

In another embodiment, step (iv) and step (v) are interchanged. In an alternative embodiment, a method for synthesizing a compound of formula IV comprises the steps of:

(i) nucleophilic attack of a compound of formula VI with a compound of formula to obtain a compound of formula II;

(ii) optional protection of the compound of formula II;

(iii) cyclization of a compound of formula II to give a compound of formula IV;

(iv) optional deprotection of the compound of formula IV; and (v) optionally oxidizing the mercapto group of formula IV to a sulfone.

In one non-limiting embodiment, a method for synthesizing a compound of formula III comprises the following steps:

(i) nucleophilic attack of a compound of formula V with a compound of formula I to obtain a compound of formula II;

(ii) optional protection of the compound of formula II;

(iii) cyclization of a compound of formula II to give a compound of formula III, where R ⁴ is H;

(iv) optional replacement of the hydrogen R ⁴ with a group other than hydrogen, which facilitates subsequent dehydration; and then (v) optionally oxidizing the mercapto group of formula III to a sulfone. In one non-limiting embodiment, a method for synthesizing a compound of formula II comprises the steps of:

(i) nucleophilic attack of a compound of formula V with a compound of formula I; and then (ii) isolating the compound of formula II.

In an alternative embodiment, a method for synthesizing a compound of formula II comprises the steps of:

(i) nucleophilic attack of a compound of formula VI with a compound of formula I; and then (ii) isolating the compound of formula II.

In an alternative embodiment, a method for synthesizing a compound of formula I comprises the steps of:

(i) reductive amination of an amine of formula VII with alkyl-2-oxoacetate to give a compound of formula VIII;

(ii) optional deprotection of the compound of formula VIII;

(iii) optional addition of a base; and then (iv) isolating the compound of formula I.

SSalkyl

In another alternative embodiment, a method for synthesizing a compound of formula I comprises the steps of:

(i) condensation of an alkylglycinate with cyclohexanone in the presence of TMSCN to give a compound of formula IX;

(ii) reduction of the cyano compound to an amine followed by subsequent intramolecular cyclization; and then (iii) isolating the compound of formula I.

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In one non-limiting example of the present invention, coupling a sulfonate to a heteroarylamine provides a compound of formula X

where Z is -(CH ₂ ) _x - where x is 1, 2, 3 or 4 or -O-(CH ₂ )z- where z is 2, 3 or 4;

R ² is independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;

each R ⁶ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of carbon in the chain and two R ^6s on adjacent ring atoms or on the same ring atom , together with the ring atom(s) to which they are attached, optionally form a 3 to 8-membered ring;

y is 0, 1, 2, 3, or 4;

R ¹² selected from:

Y is NH, O, S or NR ¹⁴ ;

X ¹ , X ² , X ³ , X ⁴ , X ⁵ are independently N or CR ¹³ where at least one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is CR ¹³ ;

R ¹³ is at each occurrence independently selected from: R ¹¹ and R ⁷ where one R ¹³ is R ⁷ ;

R ¹⁴ is selected from: -C(O)H, -C(O)alkyl, -C(8)alkyl, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;

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R ⁷ is -(alkylene)m-heterocyclo, -(alkylene)t-heteroaryl, -(alkylene)m-NR ⁸ R ⁹ , -(alkylene)m-C(O)-NR ⁸ R ⁹ ; -(alkylene)m-C(O)-O-alkyl; -(alkylene)mOR ¹⁰ , -(alkylene)mS(O) _n -R ¹⁰ or -(alkylene) _n -S(O) _n -NR ⁸ R ⁹ , any of which may optionally be independently substituted with one or more R groups ^x as far as valency permits, and where two R ^x groups bonded to the same or adjacent atom may optionally combine to form a ring, and where m is 0 or 1 and n is 0, 1 or 2;

R ⁸ and R ⁹ are each independently:

(i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may optionally be independently substituted with one or more R ^x groups, as far as valence permits, and where two R groups ^x associated with the same or adjacent atom may optionally combine to form a ring; or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached may combine to form a heterocyclic ring, optionally independently substituted with one or more R ^x groups, as far as valence permits, and where two R ^x groups associated with the same or an adjacent atom may optionally combine to form a ring;

R ¹⁰ and R ¹⁰ * in each case are:

(i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may optionally be independently substituted with one or more R ^x groups, as far as valency permits; R ^x is independently at each occurrence halogen, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene)m-OR ¹⁰ , -(alkylene)m-O-alkylene-OR ¹⁰ , -(alkylene)mS(O)nR ¹⁰ , -(αkylene)mNR8R ⁹ , -(alkylene)m-CN, -(alkylene)sh-C(O) ^ ¹⁰ , -(alkylene)m-C(S)-R ¹⁰ , -(alkylene)m-C(O)-OR ¹⁰ , -(alkylene)mO-C(O)-R ¹⁰ , -(alkylene)m -C(S)-OR ¹⁰ , -(alkylene)m-C(O)-(alkylene) _m -NR ⁸ R ⁹ , -(alkylene)m-C(S)-NR ⁸ R ⁹ , -(alkylene) mN(R ⁸ )-C(O)-NR ⁸ R ⁹ , -(alkylene)mN(R ⁸ )-C(S)-NR ⁸ R ⁹ , -(alkylene)mN(R ⁸ )-C(O) -R ¹⁰ , -(alkylene)mN(R ⁸ )-C(S)-R ¹⁰ , -(alkylene)m-O-C(O)-NR ⁸ R ⁹ , -(alkylene)t -OC(S) -NR ⁸ R ⁹ , -(alkylene)m-SO2-NR ⁸ R ⁹ , -(αkylene)m -N(R ⁸ )-SO2-R ¹⁰ , -(alkylene)mN(R ⁸ )-SO2-NR ⁸ R ⁹ , -(alkylene)mN(R ⁸ )-C(O)-OR ¹⁰ ) -(alkylene)mN(R ⁸ )-C(S)-OR ¹⁰ or -(alkylene)mN(R ⁸ )-SO2 -R ¹⁰ ;

wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) _m -CN, -(alkylene) _m - OR ¹⁰ *, -(alkylene)mS(O)nR ¹⁰ *, -(alkylene)m-NR ⁸ *R ⁹ *, -(alkylene)m-C(O)-R ¹⁰ *,-(alkylene)mC( =S)R ¹⁰ *, -(alkylene)m-C(=O)OR ¹⁰ *, -(alkylene)m-OC (=O)R ¹⁰ *, -(αkylene)m-C(S)-OR ¹⁰ *, -(alkylene)m-C(O)-NR ⁸ *R ⁹ *, -(alkylene)m-C(S)-NR ⁸ R ⁹ *, -(alkylene)mN(R ⁸ *)-C( O)NR ⁸ *R ⁹ *, -(alkylene)mN(R ⁸ *)-C(S)-NR ⁸ *R ⁹ *, -(alkylene)mN(R ⁸ *)-C(O)-R ¹⁰ *, -(alkylene)mN(R ⁸ *)-С(S)-R ¹⁰ *, -(alkylene)m-О-С(О)-NR8*R9*, -(alkylene)m-О-С( S)-NR ⁸ *R ⁹ *, -(αkylene)m-SO ₂ -NR ⁸ *R ⁹ *, -(alkylene)mN(R ⁸ *)-SO2-R ¹⁰ *, -(alkylene)mN(R ⁸ *)-SO2-NR ⁸ *R ⁹ *, -(alkylene)mN(R8*)-C(O)-OR ¹⁰ *, -(αkylene)mN(R ⁸ *)C(S)-OR ¹⁰ * or -(alkylene)mN(R ⁸ *)-SO ₂ -R ¹⁰ *, n is 0, 1 or 2;

m is 0 or 1;

R ⁸ * and R ⁹ * are in each case independently:

(i) hydrogen or (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may optionally be independently substituted with one or more R ^x groups, as far as valency permits; or

R ⁸ * and R ⁹ *, together with the nitrogen atom to which they are attached, may combine to form a heterocyclic ring, optionally independently substituted with one or more R ^x groups, as far as valence permits; and

R ¹¹ is independently selected at each occurrence from: hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl.

In a further embodiment of the present invention, coupling a sulfone to a heteroarylamine provides a compound of formula X-a

where Z is -(CH ₂ ) _x -,

- 7 042733 where x is 1, 2, 3 or 4, or-O-(CH ₂ ) _z - where z is 2, 3 or 4;

R ² is independently selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;

each R ⁶ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of carbon in the chain and two R ^6s on adjacent ring atoms or on the same ring atom , together with the ring atom(s) to which they are attached, optionally form a 3 to 8-membered ring;

y is 0, 1, 2, 3, or 4;

R ¹² selected from:

Y is NH, O, S or NR ¹⁴ ;

X ¹ , X ² , X ³ , X ⁴ , X ⁵ are independently N or CR ¹³ where at least one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is CR ¹³ ;

R ¹³ is at each occurrence independently selected from: R ¹¹ and R ⁷ where one R ¹³ is R ⁷ ;

R ¹⁴ is selected from: -C(O)H, -C(O)alkyl, -C(8)alkyl, alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl;

R ⁷ is -(alkylene)m-heterocyclo, -(alkylene)m-heteroaryl, -(alkylene)m-NR ⁸ R ⁹ , -(alkylene)m-C(O)-NR ⁸ R ⁹ ; -(alkylene)m-C(O)-O-alkyl; -(alkylene)m-O-R ¹⁰ , -(alkylene)mS(O) _n -R ¹⁰ or -(alkylene) _m -S(O) _n -NR ⁸ R ⁹ , any of which may optionally be independently substituted with one or several R ^x groups, as far as valence allows, and where two R ^x groups associated with the same or adjacent atom may optionally combine to form a ring;

R ⁸ and R ⁹ are each independently:

(i) hydrogen or (ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may optionally be independently substituted with one or more Rx groups, as far as valency permits, and where two Rx groups, associated with the same or neighboring atom, can combine to form a ring; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, may combine to form a heterocyclic ring, optionally independently substituted by one or more Rx groups, as far as valence permits, and where two Rx groups are bonded to the same or adjacent

- 8 042733 atom may optionally combine to form a ring;

R ¹⁰ is:

(i) hydrogen or (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may optionally be independently substituted with one or more R ^x groups, as far as valence permits;

R ^x is independently halogen, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkyl, n is 0, 1 or 2;

m is 0 or 1; and

R ¹¹ is independently selected at each occurrence from: hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl.

In a further embodiment, R ¹² is selected from:

In a further embodiment, R ¹² is selected from:

In a further embodiment, R ¹² is

In an additional embodiment of the present invention, the connection of the sulfone with heteroarylamine gives the compound of formula X-b

where R ¹² represents and other variables are as defined in the formula Xa.

The present invention thus includes at least the following features:

(i) a process for the synthesis of 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine starting from alkyl-4-halo-2(alkylthio)pyrimidine-5-carboxylate;

(ii) a process for the synthesis of 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine starting from 4-halo-2(alkylthio)pyrimidine-5-carbaldehyde;

(iii) a process for the synthesis of 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine from 2'-(alkylsulfonyl)lactam-n-pyrrolo[2,3-d]pyrimidine;

(iv) a process for the synthesis of 2'-(heteroaryl)lactam-n-pyrrolo[2,3-d]pyrimidine from 2'-(alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine;

(v) a process for synthesizing a compound of formula IV, comprising nucleophilic attack of a halopyrimidine with a compound of formula I, cyclization of the resulting compound, conversion of the hydroxy group to a leaving group, dehydration of the resulting compound, and optional oxidation to a sulfoxide or sulfone;

(vi) a process for synthesizing a compound of formula III, comprising nucleophilic attack of a halopyrimidine with a compound of formula I and cyclization of the resulting compound;

(vii) a method for synthesizing a compound of formula II, comprising nucleophilic attack of a halopyrimidine with a compound of formula I;

(viii) a method for synthesizing a compound of formula I; and (xi) a compound of formula II.

Brief description of the figures

Fig. 1 illustrates the synthesis of intermediate 1K from benzyl(1-(aminomethyl)cyclohexyl)carbamate. In step 1, benzyl(1-(aminomethyl)cyclohexyl)carbamate receives Boc protection. In step 2, the nucleophilic

- 9 042733 attack of the Boc-protected compound directed at 5-bromo-2,4-dichloropyrimidine provides selective displacement of chloride to obtain a dihalogen derivative. In step 3, the dihalogen derivative binds selectively, leading to the displacement of the bromide and to the production of an intramolecular alkynyl group. In steps 4-6, the intramolecular alkynyl group is cyclized to a 6-5 heteroaryl moiety. In steps 7-9, the 6-5-heteroaryl moiety is subjected to further cyclization to give intermediate 1K.

Fig. 2 illustrates the SNAr coupling of intermediate 1K to an appropriately substituted aniline compound to produce a CDK inhibitor.

Fig. 3 illustrates the gradual decrease in ppm levels of palladium from compound 10 to compounds 11, 19 and the salt of compound 19. The final concentration of palladium is 1.47%. See example 3.

Fig. 4 is formula I, formula II, formula III and formula IV.

Detailed description

I. Terminology.

Compounds are described using standard nomenclature. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

Compounds in any of the formulas described herein include racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, isomers; such as rotamers, as if each were specifically described.

The terms do not indicate a limitation of the amount, but rather indicate the presence of at least one of those described. The term or means and/or. The specification of ranges of values is only intended to be used as an abbreviated way of referring individually to each individual value falling within the range, unless otherwise noted herein, and each individual value is included in the description as if it were individually specified herein. The end values of all ranges are included within the range and are independently combined. All methods described herein can be performed in an appropriate order, unless otherwise indicated herein or otherwise clearly contrary to the context. The use of examples or illustrative expressions (eg, such as) is only intended to better illustrate the invention and does not limit the scope of the invention unless otherwise stated. Unless otherwise indicated, the technical and scientific terms used herein have the same meaning as generally understood by a person skilled in the art to which this invention belongs.

The present invention includes compounds of formula II with at least one desired isotopic substitution of an atom in an amount that is higher than the natural abundance, i. enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e. same number of protons, but different number of neutrons.

Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I, respectively. In one non-limiting embodiment of the invention, isotopically labeled compounds can be used in metabolic studies (with ¹⁴ C), kinetic studies of reactions (for example, with ² H or ³ H), in detection or imaging techniques such as positron emission tomography (positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution analyzes of drugs or substrates, or in the radioactive treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of this invention and their prodrugs can generally be prepared by following the procedures described in the Schemes or Examples, and the formulations described below can be prepared by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

As a general example and without limitation, isotopes of hydrogen, such as deuterium ( ² H) and tritium ( ³ H), can be used at any position in the described structures, which provides the desired result. Alternatively or in addition, carbon isotopes such as ¹³ C and ¹⁴ C can be used.

Isotopic substitutions, such as deuterium substitutions, may be partial or complete. Partial substitution with deuterium means that at least one hydrogen is replaced by deuterium. In some embodiments, the isotope is 90%, 95%, or 99% or more enriched in the isotope at any position of interest. In one non-limiting embodiment, the desired position is enriched in deuterium by 90%, 95%, or 99%.

In one non-limiting embodiment, the replacement of a hydrogen atom with a deuterium atom can be provided in any of A, C, L, or B. In one non-limiting embodiment, the replacement of a hydrogen atom with a deuterium atom occurs within an R group selected from any of R ¹ , R ² ,

- 10 042733

R ³ , R ^{4 , R 5 , R 6 , R 7 , R 8 , R 8 * , R 9 , R 9} *, R ¹⁰ , R ¹⁰ *, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ^x . For example, when any of the R groups is or contains, for example, by substitution, methyl, ethyl, or methoxy, the alkyl moiety may be deuterated (in non-limiting embodiments, CDH ₂ , CD ₂ H, CD ₃ , CH ₂ CD ₃ , CD ₂ , CD ₃ , CHdCh ₂ D, CH ₂ CD ₃ , CHDCHD2, OCDH2, OCD2H or OCD ₃ etc.). In some other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon atoms may be deuterated.

The compound of the present invention can form a solvate with solvents (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound. The term solvate refers to a molecular complex of a compound of the present invention (including its salt) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term hydrate refers to a molecular complex containing a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the solvent may be isotopically substituted, eg D ₂ O, d ₆ -acetone, d ₆ -DMSO. The solvate may be in liquid or solid form.

A dash (-) that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -(C=O)NH ₂ is attached through the carbon of the keto (C=O) group.

Alkyl is a saturated aliphatic hydrocarbon group with a branched or straight chain. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one non-limiting embodiment, alkyl contains from 1 to about 8 carbon atoms. In some embodiments, alkyl is C1-C2, C1-C3, or Ci-C ₆ . Specific ranges, as used herein, indicate an alkyl group having each member of the range described as an independent species. For example, the term C1- _C6 alkyl as used herein means a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each is described as being on its own. view. For example, the term C1- _C4 alkyl as used herein denotes a straight or branched alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, t-pentyl, neopentyl, n-hexyl, 2 -methylpentane, 3methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In an alternative embodiment, the alkyl group is optionally substituted.

In an alternative embodiment, when a term is used that includes alk, then cycloalkyl or carbocyclic may be considered part of the definition, unless expressly excluded from context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc. may be considered to include alkyl cyclic forms, unless this is clearly excluded by the context.

Alkoxy is an alkyl group, as defined above, covalently linked through an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy , 2-hexoxy, 3-hexoxy and 3-methylpentoxy. Similarly, an alkylthio or thioalkyl group is an alkyl group, as defined above, with the number of carbon atoms mentioned covalently bonded through a sulfur bridge (-S-). Alternatively, the alkoxy group is optionally substituted as described above. In an alternative embodiment, the thioalkyl group is optionally substituted as described above.

Amino is -NH2.

The amide or carboxamide is -C(O)NR ^a R ^b , where R ^a and R ^b are each independently selected from hydrogen, alkyl, e.g., C1-C6 alkyl, alkenyl, e.g., C2-C6 alkenyl, alkynyl , for example, C2-C6-alkynyl, -C0-C4-alkyl(C3-C7-cycloalkyl), -C0-C4-alkyl(C3-C7-heterocycloalkyl), -Co-C4-alkyl(aryl) and -C0-C4- alkyl(heteroaryl); or, together with the nitrogen to which they are bonded, R ^a and R ^b may form a C3- _C7 heterocyclic ring. In an alternative embodiment, the R ^a and R ^b groups are each independently optionally substituted as described above.

As used herein, the term carbocyclyl, carbocyclic, carbocycle, or cycloalkyl is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon atoms of the ring and from 3 to 14 ring carbon atoms (C ₃ - ₁₄ carbocyclyl) and zero heteroatoms in a non-aromatic ring system. In some embodiments, the implementation of the carbocyclyl group has from 3 to 10 carbon atoms in the ring (C ₃ - ₁₀ -carbocyclyl). In some embodiments, the implementation of the carbocyclyl group has from 3 to 9 ring carbon atoms (C ₃ - ₉ -carbocyclyl). In some embodiments, the implementation of the carbocyclyl group has from 3 to 8 ring carbon atoms (C ₃ _ ₈ -carbocyclyl). In some embodiments, the implementation of the carbocyclyl group has from 3 to 7 ring carbon atoms (C ₃ _ ₇ -carbocyclyl). In some variants

- 11 042733 implementation carbocyclyl group has from 3 to 6 ring carbon atoms (C _3-6 carbocyclyl). In some embodiments, the implementation of the carbocyclyl group has from 4 to 6 ring carbon atoms (C _4-6 -carbocyclyl). In some embodiments, the implementation of the carbocyclyl group contains from 5 to 6 carbon atoms in the ring (C _5-6 -carbocyclyl). In some embodiments, the implementation of the carbocyclyl group has from 5 to 10 carbon atoms in the ring (C _5-10 -carbocyclyl). Exemplary C _3-6 carbocyclyl groups include, without limitation, cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl (C ₅ ), cyclopentenyl (C ₅ ), cyclohexyl (C ₆ ), cyclohexenyl (C ₆ ), cyclohexadienyl (C ₆ ) and the like. Exemplary C _3-8 carbocyclyl groups include, without limitation, the aforementioned C _3-6 carbocyclyl groups, as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl ( C ₈ ), cyclooctenyl (C ₈ ) and the like. Exemplary C _3-10 carbocyclyl groups include, without limitation, the aforementioned C _3-8 carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ) and the like. As the examples above show, in certain embodiments, the implementation of the carbocyclyl group may be saturated or may contain one or more carbon-carbon double or triple bonds. In an alternative embodiment, carbocyclyl also includes ring systems in which the carbocyclyl ring, as defined above, is fused to one or more heterocyclyl, aryl, or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, in which case the number of carbons continues to denote the number of atoms carbon in a carbocyclic ring system. In an alternative embodiment, each occurrence of the carbocycle is optionally substituted with one or more substituents. In some embodiments, the carbocyclyl group is an unsubstituted C _3-14 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C _3-14 carbocyclyl.

Haloalkyl refers to both straight and branched alkyl groups substituted with 1 or more halogen atoms, up to the maximum number of halogen atoms allowed. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

Haloalkoxy refers to a haloalkyl group, as defined herein, attached via an oxygen bridge (the oxygen of the alcohol radical).

Halo or halogen independently denotes fluorine, chlorine, bromine or iodine.

As used herein, the term aryl refers to the radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the cyclic array) having 6 to 14 carbon atoms. in the ring and zero heteroatoms (C _6-14 -aryl). In some embodiments, the implementation of the aryl group has 6 carbon atoms in the ring (C ₆ -aryl; for example, phenyl). In some embodiments, the implementation of the aryl group has 10 carbon atoms in the ring (C ₁₀ -aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the implementation of the aryl group has 14 carbon atoms in the ring (C ₁₄ -aryl; for example, anthracyl). Aryl also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, in which case the carbon number continues to denote the number of carbon atoms in the aryl ring. system. One or more fused carbocyclyl or heterocyclyl groups may be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups which optionally contain 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron to form, for example, a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, the aryl groups are pendant (pendant). An example of a pendant ring is a phenyl group substituted with a phenyl group. In an alternative embodiment, the aryl group is optionally substituted as described above. In some embodiments, the aryl group is an unsubstituted C _6-14 aryl. In some embodiments, the aryl group is a substituted C _6-14 aryl.

Arylalkyl is an aryl group, as defined herein, attached via an alkyl group. Non-limiting examples of arylalkyl groups include:

g , , s' and ^v .

Aryloxy is an aryl group, as defined herein, attached via a -O- linker. Non-limiting examples of aryloxy groups include:

- 12 042733

Alkylsulfinyl and alkyl sulfoxide, as defined herein, are represented as

alkyl alkyl * o

II o

Alkylsulfonyl and alkylsulfone, as defined herein, are represented as alkyl yl

II. Coupling of heteroaryl amines with sulfones/sulfoxides.

It has been found that 2'-(heteroaryl)lactam-pyrrolo[3,2-d]pyrimidines are predominantly prepared by coupling an alkylsulfone or alkylsulfoxide-substituted condensed pyrimidine with a heteroarylamine to form a central disubstituted amine. The use of an alkylsulfone or alkylsulfoxide substituted fused pyrimidine instead of a chlorine substituted fused pyrimidine increases the yield of the conjugated diamine product and lowers the required temperature, resulting in fewer by-products and hence impurities.

Typically, the coupling may take place in a polar aprotic solvent at reduced temperature, if desired, in the presence of a base which facilitates the reaction. For example, coupling can be achieved by adding a sulfonate to a stirred solution of heteroarylamine in THF at or below room temperature in the presence of LiHMDS. While different orders of addition are possible to give a comparable result, the amine is preferably added last to reduce the occurrence of dimerization side reactions.

In one non-limiting embodiment, the pyrimidine is fused to a pyrrole/spirocyclic lactam ring system. For example, the sulfone may be 2'(methylsulfonyl)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3d ]pyrimidine]-6'-one or its derivative.

In an alternative embodiment, the pyrimidine is fused to a pyrrole/cyclic lactam system. For example, the sulfone may be 2-(methylsulfonyl)-8,9dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin-6(7H)-one or a derivative thereof.

Step 1. Method for adding heteroaryl amines to sulfones/sulfoxides.

In step 1, heteroarylamine is reacted with 2'-(alkylsulfonyl)lactam-pyrrolo[2,3d]pyrimidine or 2'-(alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine in the presence of a base to give 2'- (heteroaryl)lactam-pyrrolo[2,3-d]n-pyrimidine. The heteroarylamine is mixed with a suitable base in a suitable solvent, usually a neutral organic solvent, in which both reactants are soluble. 2'-(alkylsulfonyl)lactam-pyrrolo[2,3d]pyrimidine or 2'-(alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine is then added in one or more portions. Any molar ratio of the two reactants that achieves the desired results can be used. Typically, an excess of heteroarylamine is used, eg about 3 equiv. heteroarylamine to about 1.0 equiv. sulfone or sulfoxide. The reaction can be carried out at any temperature that allows the reaction to take place. It was found that the reaction can be carried out at a temperature below room temperature. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 2'-(heteroaryl)lactampyrrolo[2,3-d]pyrimidine. In one non-limiting illustrative embodiment, heteroarylamine is 5-(4-methylpiperazin-1-yl)pyridin-2-amine, 2'-(alkylsulfonyl)lactampyrrolo[2,3-d]pyrimidine is 2'-(methylsulfonyl)- 7',8'-dihydro-6'H-spiro[cyclohexane1,9'-pyrazino[1',2':1,5]n-pyrrolo[2,3-d]pyrimidine]-6'-1, the base is LiHMDS, the solvent is THF, the temperature is about 5°C, the reaction time is about an hour.

The base used in Step 1 may be any suitable base including but not limited to LiHMDS, NaHMDS, NaH, KH, LDA, DIPEA (N,Ndiisopropylethylamine), DMAP (4-dimethylaminopyridine), DBU (1.8 -diazabicycloundec-7-ene), TEA (triethylamine), pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine , methylbenzylamine, dimethylbenzylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, proton sponge , 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine or Trizma. In one non-limiting embodiment, the base is selected from LiHMDS, NaHMDS, NaH, KH, and LDA. In an alternative embodiment, multiple bases are used in step 1.

The solvent used in step 1 may be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (dichloromethane), THF (tetrahydrofuran), DMF (N,N-dimethylformamide), ACN (acetonitrile), DMAP (4dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (dimethoxyethane) , DMSO (dimethyl sulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (hexamethylphosphoramide), methanol, MTBE (methyl tertiary butyl ether), NMP (N-methyl-2-pyrrolidone), pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from THF, ACN, DMAP and DMSO. In an alternative embodiment, step 1 uses a mixture of solvents.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The temperature used in step 1 may be, for example, about 20 to about 25°C, about 15 to about 30°C, about 10 to about 35°C, about 5 to about 40°C, or about 0 to about 50°C. In one non-limiting embodiment, the temperature is maintained at or below room temperature. Alternatively, although less typically, the reaction may be carried out at elevated temperatures.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 1 for about 10 minutes to about 10 hours, about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, or about 1 to about 2 hours.

In one embodiment, the crude reaction mixture is quenched with water. In another embodiment, the crude reaction mixture is quenched with saturated ammonium chloride.

In one embodiment, the sulfone is added in portions with mixing intervals of at least about 5, 10, 15, or 20 minutes. In one embodiment, the sulfone is added in portions with a mixing interval of at least 10 minutes.

In one embodiment, 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine is used as the free base. In another embodiment, the 2'-(heteroaryl)lactam-pyrrolo[2,3d]pyrimidine is converted to a salt (eg, step 2).

In one embodiment, 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine is a compound of formula X.

WO 2013/163239 and WO 2015/061407 describe the addition of heteroarylamine to lactampyrrolo[2,3-d]pyrimidine via a leaving group selected from Cl, Br, I, -S-Me, -S-aryl, -Sheteroaryl, SOMe, SCO ₂ Me, SO-alkyl, SO ₂ -alkyl, SO-cycloalkyl, SO ₂ -cycloalkyl, SO-aryl, SO ₂ aryl, hydroxy, hydroxyalkyl, hydroxyaryl and hydroxyheteroaryl.

Step 2. Process for preparing the 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine salt.

In step 2, 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine is reacted with an acid to form a 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine salt. The 2'-(heteroaryl))-lactam-pyrrolo[2,3d]pyrimidine is mixed with the appropriate acid in a suitable solvent, usually a neutral organic solvent, in which both reactants are soluble. In one embodiment, the solvent is an acid. In addition to the first solvent and acid, an anti-solvent may be used. Any molar ratio of the two reactants that achieves the desired results can be used. Usually an excess of acid is used. The reaction can be carried out at any temperature that allows the reaction to take place. It was found that the reaction can be carried out at room temperature. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the 2'-(heteroaryl)lactam-pyrrolo[2,3-d]pyrimidine salt.

In one embodiment, the acid is HCl.

The solvent used in step 2 may be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (dichloromethane), THF (tetrahydrofuran), DMF (N,N-dimethylformamide), ACN (acetonitrile), DMAP (4dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (dimethoxyethane) , DMSO (dimethyl sulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (hexamethylphosphoramide), methanol, MTBE (methyl tert-butyl ether), NMP (N-methyl2-pyrrolidone), pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from THF, ACN, DMAP and DMSO. In an alternative embodiment, step 2 uses a mixture of solvents.

In one embodiment, the solvent is about 6 M aqueous HCl. In another embodiment, the solvent is about 4M HCl in dioxane. In another embodiment, the solvent is a mixture of solvents. In one embodiment, the solvent mixture is a mixture of DCM and methanol.

In an additional embodiment, the solvent is about 2 M aqueous HCl. In another additional embodiment, the solvent is 2M aqueous HCl.

The anti-solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (dichloromethane), THF (tetrahydrofuran), DMF (N,N-dimethylformamide) , ACN (acetonitrile), DMAP (4dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (dimethoxyethane ), DMSO (dimethyl sulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (hexamethylphosphoramide), methanol, MTBE (methyl tert-butyl ether), NMP (N-methyl2-pyrrolidone), pentane, pyridine, toluene, hydrochloric acid acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, methanol, acetone and DMSO. In an alternative embodiment, step 2 uses a mixture of solvents.

The temperature used in step 2 may be, for example, from about 20 to about 25°C, from about 15 to about 30°C, from about 10 to about 35°C, from about 5 to about 40°C, from about 0 to about 50°C or from about 0 to about 70°C. In one non-limiting embodiment, the temperature is maintained at or below room temperature. Alternatively, although less typically, the reaction may be carried out at elevated temperatures.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 2 for about 10 minutes to about 10 hours, about 30 minutes to about 5 hours, about 45 minutes to about 3 hours, or about 1 to about 2 hours.

In one embodiment, the salt is a di-HCl salt.

IIIA. Process for preparing sulfone/sulfoxide from pyrimidine ester.

It has been found that 2'-(alkylsulfonyl)lactam-pyrrolo[2,3-d]n-pyrimidines, as well as sulfoxide and sulfide analogs, can also be prepared in seven steps or less from alkyl-4-halo2-(alkylthio)pyrimidine-5 -carboxylates. In one non-limiting embodiment, the 2'(alkylsulfonyl)lactam-pyrrolo[2,3-b]pyrimidine is a spirocycle, e.g., 2'(methylsulfonyl)-7',8'-dihydro-6H-spiro[cyclohexane-1,9 '-pyrazino[1',2': 1,5]pyrrolo[2,3d]pyrimidine]-6'-one.

Stage 1. Obtaining alkyl-2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.

Alkylo

In step 1, alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate reacts with amino lactam in a nucleophilic substitution reaction to give alkyl 2-(alkylthio)-4-(lactam)pyrimidine 5-carboxylate. The alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate and the amino lactam are mixed in a suitable solvent, usually a neutral organic solvent, which dissolves both reactants together with a base which will promote the nucleophilic substitution reaction. Any molar ratio of the two reactants that achieves the desired results can be used. Typically, a small molar excess of the amino lactam is used, eg about 1.1 equiv. amino lactam and about 1.0 equiv. carboxylate. The reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be facilitated by heating, including up to boiling, under reflux. The reactions are allowed sufficient time to provide the desired yield, after which the batch is optionally cooled and purified by any suitable method, including filtration, crystallization and column chromatography, to give alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate. In one non-limiting illustrative embodiment, the alkyl-4-halo-2(alkylthio)pyrimidine-5-carboxylate is ethyl 4-chloro-2-(methylthio)pyrimidine-5carboxylate, the aminolactam is spirolactam, the base is DIPEA, the solvent is DMAc, temperature corresponds to about 95°C, time is about 60 hours.

The base used in step 1 may be any suitable organic base, including but not limited to DIPEA (N,N-diisopropylethylamine), DMAP (4dimethylaminopyridine), DBU (1,8-diazabicycloundec-7-ene), TEA (triethylamine), pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline,

- 15 042733 pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO (1,4diazabicyclo[2.2.2]octane), 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine, proton sponge, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, TEA, and pyridine. In an alternative embodiment, multiple bases are used in step 1.

The solvent used in step 1 may be any suitable organic solvent, including but not limited to DMAc (N,N-dimethylacetamide), DCM (dichloromethane), THF (tetrahydrofuran), DMF (K,K-dimethylformamide), ACN (acetonitrile), DMAP (4dimethylaminopyridine), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME (dimethoxyethane) , DMSO (dimethyl sulfoxide), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA (hexamethylphosphoramide), methanol, MTBE (methyl tertiary butyl ether), NMP (N-methyl-2-pyrrolidone), pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from THF, ACN, DMAP and DMSO. In an alternative embodiment, step 1 uses a mixture of solvents.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The temperature used in step 1 may be, for example, about 50 to about 150°C, about 60 to about 125°C, about 70 to about 110°C, about 80 to about 100°C, or about 90 to about 100°C. In one non-limiting embodiment, the temperature is selected from about 80 to about 100°C. In an alternative embodiment, the reaction temperature is maintained above the boiling point of the solvent using a reaction vessel that can support elevated pressures. Alternatively, although less typically, the reaction may be carried out at or below room temperature.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 1 for about 5 to about 110 hours, about 15 to about 100 hours, about 25 to about 90 hours, about 35 to about 80 hours, or about 50 to about 70 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield.

Step 2: Optional protection of alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate.

Alkylo ।

In Step 2, alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is reacted with a protecting group reagent to form a protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate. Alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate and the protecting group reagent are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants dissolve together with the base, which will facilitate the introduction of the protecting group . Any molar ratio of the two reactants that achieves the desired results can be used. Typically, a small molar excess of the protecting group reagent is used, eg about 1.5 equiv. protecting group reagent and about 1.0 equiv. alkyl-2-(alkylthio)-4-(lactam)pyrimidine5-carboxylate. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5carboxylate. In one non-limiting embodiment, the alkyl 2-(alkylthio)-4(lactam)pyrimidine-5-carboxylate is ethyl 2-(methylthio)-4-(3-oxo-1,4diazaspiro[5.5]undecan-1-yl )pyrimidine-5-carboxylate, the protecting group reagent is Boc anhydride, the base is DMAP, the solvent is dichloromethane, the temperature is about 25°C, and the time is about 3 hours.

In one non-limiting embodiment, the original amino lactam used has already been protected. In an alternative embodiment, the lactam-substituted pyrimidine reacts appropriately without the need for a protecting group.

The protecting group reagent used in step 2 can be any suitable reagent that allows the introduction of any suitable protecting group, including, but not limited to, Boc anhydride (tert-butyloxycarbonyl anhydride), Boc-Cl, CBz-Cl, ( carboxybenzyl chloride - 16 042733) methyl chloroformate, benzyl chloride, benzoyl chloride, allyl chloride, triflic anhydride, TfCl, tosyl anhydride and Ts-Cl. In one non-limiting embodiment, the protecting group is Boc and the suitable reactant is either Boc anhydride or Boc-Cl. In an alternative embodiment, the protecting group is CBz and a suitable reagent is CBz-Cl.

The base used in step 2 may be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperidine, proton sponge, 1,5,7triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, and Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, TEA, and pyridine. In an alternative embodiment, multiple bases are used in step 2.

The solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water and THF. In an alternative embodiment, step 2 uses a mixture of solvents.

The temperature used in step 2 may be, for example, about -20 to about 100°C, about -10 to about 80°C, about 0 to about 60°C, about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 2 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours. Those skilled in the art will recognize that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 3: Preparation of 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

Alkyl _y |_ _s <

In step 3, a protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate reacts with a base in intramolecular cyclization to give 5'-hydroxy-2'-(alkylthio)lactampyrrolo[2,3-d]pyrimidine . The protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate and the base are mixed in a suitable solvent, typically a neutral organic solvent, in which both the reactant and the reagent are dissolved. Any molar ratio of reactant to reagent can be used to achieve the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine. In one non-limiting embodiment, the protected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is t-butyl-1-(5-(ethoxycarbonyl)-2-(methylthio)pyrimidin-4-yl) -3-oxo-1,4diazaspiro[5.5]undecane-4-carboxylate, the base is DBU, the solvent is THF, the temperature is about 5°C, and the time is about 2 hours.

The base used in step 3 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperidine, proton sponge, 1,5,7triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or

- 17 042733

trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP,

DBU, DABCO, TEA and pyridine. In an alternative embodiment, multiple bases are used in step 3.

The solvent used in step 3 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water and THF. In an alternative embodiment, a mixture of solvents is used in step 3.

The temperature used in step 3 may be, for example, about -50 to about 50°C, about -35 to about 40°C, about -10 to about 30°C, about -5 to about 20°C. or from about 0 to about 10°C. In one non-limiting embodiment, the temperature is selected from about 0 to about 10°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 4. Preparation of the 5'-leaving group of 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

In Step 4, 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine reacts with a leaving group reagent to form a 5'-leaving group-2'-(alkylthio)lactam-pyrrolo[ 2,3d]pyrimidine. The 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine and the leaving group reagent are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants dissolve together with the base, which facilitate the reaction. Any molar ratio of reactants that achieves the desired results can be used. Typically, a small molar excess of the protecting group reagent is used, eg, about 1.6 equiv. leaving group reagent and about 1.0 equiv. 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the 5'-leaving group-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine . In one non-limiting embodiment, the 5'-hydroxy-2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine is t-butyl-5'-hydroxy-2'-(methylthio)-6'-oxo-6' N-spiro[cyclohexane1,9'-pyrazino[G,2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate, leaving group reagent is triflic anhydride, base is TEA, the solvent is DCM, the temperature is about 0°C, and the time is about 3 hours.

The leaving group reagent used in step 4 can be any suitable reagent that allows the conversion of a hydroxyl group to any suitable leaving group, including, but not limited to, triflic anhydride, Tf-Cl, tosyl anhydride, and Ts-Cl. In one non-limiting embodiment, the protecting group is a triflate and a suitable reagent is either triflic anhydride or Tf-Cl.

The base used in step 4 may be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperidine, proton sponge, 1,5,7triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, trimethylamine, TEA, and pyridine. In an alternative embodiment, multiple bases are used in step 4.

- 18 042733

The solvent used in step 4 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, diethyl ether and THF. In an alternative embodiment, a mixture of solvents is used in step 4. Typically, the solvent or mixture of solvents is aprotic to avoid reaction with the leaving group reagent.

The temperature used in step 4 may be, for example, about -50 to about 50°C, about -35 to about 35°C, about -25 to about 25°C, about -15 to about 15°C. C or from about -5 to about 5°C. In one non-limiting embodiment, the temperature is selected from about -5 to about 5°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 4 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours. Those skilled in the art will recognize that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 5: Preparation of 2'-(αkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

ABOUT

In step 5, the 5'-leaving group-2'-(αkylthio)lactam-pyrrolo[2,3-d]pyrimidine is reacted with a leaving group cleaving reagent to remove the leaving group to give the 2'(αkylthio))lactam- pyrrole[2,3-d]pyrimidine. The 5'-leaving group-2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine and the leaving group cleaving reagent are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants are dissolved together with the catalyst which will facilitate the reaction. Any molar ratio of reactants that achieves the desired results can be used. As a rule, take a molar excess of the reagent, cleaving the leaving group, for example, about 2.0 equiv. leaving group cleaving reagent and 1.0 equiv. 5'-leaving group of 2'-(αkylthio)lactam-pyrrolo[2,3-d]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 2'-(αkylthio)lactam-pyrrolo[2,3-d]pyrimidine. In one non-limiting embodiment, the 5'-leaving group-2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine is t-butyl-2'(methylthio)-6'-oxo-5'-(( (trifluoromethyl)sulfonyl)oxy)-6'H-spiro[cyclohexane-1,9'pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8Ή)-carboxylate , the leaving group cleavage reagent is triethylsilane, the catalyst is palladium tetrakis, the solvent is DMF, the temperature is about 50°C, and the time is about 14 hours.

The leaving group cleavage agent used in step 5 can be any suitable reagent that allows the removal of a leaving group, including, but not limited to, trialkylsilanes. In one non-limiting embodiment, the leaving group cleavage reagent is triethylsilane.

The catalyst used in Step 5 may be any suitable organometallic catalyst including, but not limited to, Pd/C, tetrakis-palladium, palladium acetate, [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II), tris( dibenzylideneacetone)dipalladium(0) and allylpalladium(II) chloride. In an alternative embodiment, multiple catalysts or a catalyst and a co-catalyst are used in step 5.

The solvent used in step 5 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DMF, DMSO, ACN, and NMP. Alternatively, a mixture of solvents is used in step 5. Typically the solvent or mixture of solvents is aprotic to avoid reaction with the reagent.

The temperature used in step 5 may be, for example, about 0 to about 100°C, about 15 to about 85°C, about 25 to about 75°C, about 35 to about 65°C, or about 45 up to about

55°C. In one non-limiting embodiment, the temperature is selected from about 45 to about

55°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 5 for about 1 to about 30 hours, about 3 to about 25 hours, about 6 to about 20 hours, about 9 to about 16 hours, or about 12 to about 15 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 6: Optional deprotection of 2'-(alkylthio)lactam-pyrrolo[2,3b]pyrimidine.

Step 6 deprotects the 2'-(alkylthio)lactam-pyrrolo[2,3-4]pyrimidine to give a deprotected alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate. The 2'(alkylthio)lactam-pyrrolo[2,3-b]pyrimidine and the deprotecting reagent are mixed in a suitable solvent, usually an organic solvent, in which both reactants are soluble. Any molar ratio of reactant and deprotecting agent that achieves the desired results can be used. Typically, a large molar excess of the deprotecting reagent is used, eg about 5 equiv. reagent to remove the protective group and about 1.0 equiv. 2'-(alkylthio))-lactam-pyrrolo[2,3-b]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. Sufficient time is allowed for the reaction to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the deprotected alkyl-2-(alkylthio)-4-(lactam)pyrimidine. In one non-limiting embodiment, the 2'-(alkylthio)lactam-pyrrolo[2,3-b]pyrimidine is t-butyl-2'-(methylthio)-6'-oxo-6'H-spiro[cyclohexane-1, 9'-pyrazino[1,2':1,5]pyrrolo[2,3b]pyrimidine]-7'(8'H)-carboxylate, deprotecting agent is TFA, solvent is dichloromethane, temperature is about 25°C and the time is about 2 hours.

In one non-limiting embodiment, 2'-(alkylthio)lactam-pyrrolo[2,3b]pyrimidine has already been deprotected because it was suitable for carrying out the preceding reactions in the absence of a protecting group. Alternatively, the protecting group is left to be removed at a later stage.

The deprotecting agent used in step 6 may be any suitable reagent that allows the deprotection of any suitable protecting group, including, but not limited to, TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzenesulfonic acid, benzoic acid , formic acid, lactic acid, malic acid, malonic acid, methanesulfonic acid, oxalic acid, phthalic acid, salicylic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid , hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, iodic acid, p-hostic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with hydrogen gas, triethylsilane, TBAF, and HF. In one non-limiting embodiment, the protecting group is Boc and the suitable reagent is TFA. In an alternative embodiment, the protecting group is CBz and a suitable reactant is palladium on carbon with hydrogen gas.

In a further embodiment, the deprotecting agent used in step 6 is a basic deprotecting agent including, but not limited to, DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine , dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2 ,6-lufinoline, 2,6-20 042733 lufinoline piperazine, proton sponge, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, KH or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, DABCO, TEA, and tBuOK.

In a further embodiment, the deprotecting reagent used in step 6 is NaOMe.

In another additional embodiment, MeOH is used as the solvent for deprotection with NaOMe as the base. In one embodiment, the reaction mixture is heated for about 1, 2, 3, 4, 5, 6, 7, or 8 hours. In one embodiment, the reaction mixture is cooled below room temperature before isolation. In one embodiment, the reaction mixture is refluxed for about 3 hours, cooled to about 0° C., isolated and washed with MeOH.

The solvent used in step 6 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from TFA, DCM, THF, and chloroform. In an alternative embodiment, step 6 uses a mixture of solvents. In another alternative embodiment, a deprotecting agent is used as the solvent.

The temperature used in step 6 may be, for example, about -20 to about 100°C, about -10 to about 80°C, about 0 to about 60°C, about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 6 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 7: Optional oxidation of 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

In step 7, 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine reacts with an oxidizing agent to give 2'-(alkylsulfonyl)lactam-pyrrolo[2,3-b]pyrimidine or 2'-(alkylsulfinyl ) lactamyrrolo[2,3]pyrimidine. The 2'-(Alkylthio)lactam-pyrrolo[2,3-b]pyrimidine and oxidizing agent are mixed in a suitable solvent, usually a neutral organic solvent, which dissolves both reactants. You can use any molar ratio of reactant and oxidant that achieves the desired results. Typically, a large molar excess of the oxidizing agent is used, for example, about 5 equiv. oxidizing agent and about 1.0 equiv. 2'-(alkylthio))-lactam-pyrrolo[2,3e]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 2'-(alkylsulfonyl)lactam-pyrrolo[2,3-b]pyrimidine or 2'(alkylsulfinyl) lactam-pyrrolo[2,3-d]pyrimidine. In one non-limiting embodiment, the 2'-(alkylthio)lactam-pyrrolo[2,3-b]pyrimidine is 2'-(methylthio)-7',8'-dihydro-6'Hspiro[cyclohexane-1,9'- pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one, the oxidizing agent is oxone, the solvent is a mixture of water and acetonitrile, the temperature is about 25°C, and the time is about 2 hours.

The oxidizing agent used in step 7 can be any suitable reagent that provides oxidation to the sulfone or sulfoxide oxidation state, including, but not limited to, oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite. In one non-limiting embodiment, the product is a sulfone and the oxidizing agent is an oxone.

In a further embodiment, the oxidant used is catalyzed by an additive. In one embodiment, the additive is Na ₂ WO ₄ . In one embodiment, the additive is Na ₂ WO ₄ and the oxidizing agent is hydrogen peroxide. In one embodiment, the additive is Na ₂ WO ₄ and the oxidizing agent is hydrogen peroxide and the reaction is carried out in a mixture of H 2 O and EtOH with heating. In one embodiment, the additive is Na ₂ WO ₄ and the oxidizing agent is hydrogen peroxide and the reaction is carried out in a mixture of H 2 O and EtOH at about 60°C for about 1, 2, 3, 4, 5, 6, 7, 8 or 9 o'clock

In an additional embodiment, the oxidizing agent is slowly added to the reaction mixture. In one embodiment, the oxidant is added over about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 minutes. In one embodiment, the oxidant is added over about 50 minutes. In one embodiment, a 50 minute addition results in a higher yield than a faster addition such as a 10 minute addition.

The solvent used in step 7 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from ACN, water and dioxane. In an alternative embodiment, step 7 uses a mixture of solvents, eg water and ACN.

The temperature used in step 7 may be, for example, about -20 to about 100°C, about -10 to about 80°C, about 0 to about 60°C, about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 7 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

One skilled in the art will appreciate that the order of steps prescribed herein may change while achieving the same end product. For example, the oxidation can be carried out between stages 3 and 4, between stages 4 and 5, or between stages 5 and 6; the protection step may be performed prior to step 1, between step 3 and step 4, or between step 4 and step 5; the deprotection step may be performed between steps 3 and 4, between steps 4 and 5, or after step 7.

In one non-limiting embodiment, the amino lactam is already adequately protected and step 2 is not necessary. In another embodiment, the selected reagents and starting materials do not need protection to proceed to the desired product, and step 2 and step 6 are not necessary.

In another embodiment, the aminolactam is a compound of formula I, alkyl2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of formula II, 5'hydroxy-2'-(alkylthio))lactam-pyrrolo[2, 3-d]pyrimidine and 5'-leaving group-2'-(alkylthio)lactampyrrolo[2,3-d]pyrimidine are compounds of formula III, and 2'-(alkylthio)lactampyrrolo[2,3-d]pyrimidine is is a compound of formula IV.

IIIB. Method for producing sulfone/sulfoxide from pyrimidine aldehyde.

It has been found that 2'-(alkylthio))-lactam-pyrrolo[2,3-b]pyrimidines, as well as their sulfoxide and sulfide analogs, can be prepared in five or fewer steps from 4-halo-2(alkylthio)pyrimidine -5-carbaldehydes. In one non-limiting embodiment, the 2'(alkylthio)lactam-pyrrolo[2,3-b]pyrimidine is a spirocycle, e.g., 2'(methylsulfonyl)-7',8'-dihydro-6'H-spiro[cyclohexane-1 ,9'-pyrazino[1',2':1,5]pyrrolo[2,3d]pyrimidine]-6'-one.

Stage 1. Obtaining 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.

In step 1, 4-halo-2-(alkylthio)pyrimidine-5-carbaldehyde reacts with amino lactam in a nucleophilic substitution reaction to give 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde. The 4-halogen-2-(alkylthio)pyrimidine-5-carbaldehyde and the amino lactam are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants dissolve in together with a base which will promote the nucleophilic substitution reaction. . Any molar ratio of the two reactants that achieves the desired results can be used. Typically, a small molar excess of the amino lactam is used, eg about 1.1 equiv. amino lactam and about 1.0 equiv. carbaldehyde. The reaction can be carried out at any temperature that allows the reaction to take place. It has been found that the reaction can be facilitated by heating, including up to reflux. The reactions are allowed sufficient time to provide the desired yield, after which the batch is optionally cooled and the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde. In one non-limiting embodiment, the 4-halo-2-(alkylthio)pyrimidine-5-carbaldehyde is 4-chloro-2-(methylthio)pyrimidine-5-carbaldehyde, the aminolactam is spirolactam, the base is DIPEA, the solvent is tert -butanol, the temperature is about 85°C, and the time is about 24 hours.

The base used in step 1 can be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine , tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6lutidine, morpholine, piperidine, piperidine, proton sponge, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, TEA, and pyridine. In an alternative embodiment, multiple bases are used in step 1.

The solvent used in step 1 may be any suitable organic solvent including, but not limited to, DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DMAc, t-butanol, DMAP and DMSO. In an alternative embodiment, step 1 uses a mixture of solvents.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The temperature used in step 1 in non-limiting examples may be from about 50 to about 150°C, from about 60 to about 125°C, from about 70 to about 110°C, from about 80 to about 100°C, or from about 90 to about 100°C. In one non-limiting embodiment, the temperature is selected from about 80 to about 100°C. In an alternative embodiment, the reaction temperature is maintained above the boiling point of the solvent using a reaction vessel that can withstand elevated pressure. Alternatively, although the reaction is less typical, the reaction can be carried out at or below room temperature.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 1 for about 1 to about 65 hours, about 7 to about 55 hours, about 12 to about 45 hours, about 17 to about 35 hours, or about 22 to about 25 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield.

Step 2: Optional protection of 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde.

In Step 2, 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is reacted with a protecting group reagent to give protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde. The 2(Alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde and the protecting group reagent are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants are dissolved together with a base which will facilitate the introduction of the protecting group. Any molar ratio of the two reactants that achieves the desired results can be used. Generally, a large molar excess of the protecting group reagent is used, eg about 7 equiv. protecting group reagent and about 1 equiv. 2-(alkylthio)-4-(lactam)pyrimidine-5carbaldehyde. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after

- 23 042733 whereby the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to obtain protected 2-(alkylthio)-4-(lactam)pyrimidine-5carbaldehyde. In one non-limiting embodiment, 2-(alkylthio)-4(lactam)pyrimidine-5-carbaldehyde is 2-(methylthio)-4-(3-oxo-1,4diazaspiro[5.5]undecan-1-yl)pyrimidin-5 -carbaldehyde, the protecting group reagent is Boc anhydride, the base is DMAP, the solvent is dichloromethane, the temperature is about 25°C, and the time is about 3 hours.

In one non-limiting embodiment, the original amino lactam used has already been protected. In an alternative embodiment, the lactam-substituted pyrimidine reacts appropriately without the need for a protecting group.

The protecting group reagent used in step 2 can be any suitable reagent that allows the introduction of any suitable protecting group, including, but not limited to, Boc anhydride, Boc-Cl, CBz-Cl, methyl chloroformate, benzyl chloride, benzoyl chloride, allyl chloride, triflic anhydride, Tf-Cl, tosyl anhydride and Ts-Cl. In one non-limiting embodiment, the protecting group is Boc and either Boc anhydride or Boc-Cl is a suitable reagent. In an alternative embodiment, the protecting group is CBz and the suitable reagent is CBz-Cl.

The base used in step 2 may be any suitable organic base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperidine, proton sponge, 1,5,7triazabicyclo[4.4.0]deca-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, and Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, TEA, and pyridine. In an alternative embodiment, multiple bases are used in step 2.

The solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water and THF. In an alternative embodiment, a mixture of solvents is used in step 2.

The temperature used in step 2 in non-limiting examples may be from about -20 to about 100°C, from about -10 to about 80°C, from about 0 to about 60°C, from about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 2 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 3. Obtaining 2'-(alkylthio)lactam-pyrrolo[2,3-b]pyrimidine.

In step 3, optionally protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is reacted with a base in intramolecular cyclization to give 2'-(alkylthio))lactampyrrolo[2,3-b]pyrimidine. The protected alkyl-2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde and the base are mixed in a suitable solvent, usually a neutral organic solvent, in which both the reactant and the reagent are dissolved. Any molar ratio of reactant to reagent can be used to achieve the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified

- 24 042733 by any suitable method, including filtration, crystallization and column chromatography, to obtain 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine. In one non-limiting embodiment, the protected 2-(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is t-butyl-2'-(methylthio)-6'-oxo-6H-spiro[cyclohexane-1,9' -pyrazino[1,2':1,5]pyrrolo[2,3d]pyrimidine]-7'(8Ή)-carboxylate, the base is tBuOK, the solvent is THF, the temperature is about 5°C, and the time is about 2 h.

The base used in step 3 may be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine , tripropylamine, tripropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperidine, piperazine , proton sponge 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, KH, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, DABCO, TEA, and tBuOK. In an alternative embodiment, multiple bases are used in step 3.

The solvent used in step 3 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water, and TFIF. In an alternative embodiment, a mixture of solvents is used in step 3.

The temperature used in step 3 in non-limiting examples may be from about -50 to about 50°C, from about -35 to about 40°C, from about -10 to about 30°C, from about -5 to about 20° C or from about 0 to about 10°C. In one non-limiting embodiment, the temperature is selected from about 0 to about 10°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 4: Optional deprotection of 2'-(alkylthio)lactam-pyrrolo[2,3b]pyrimidine.

ABOUT

Step 4 deprotects the 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine to give deprotected 2'-(alkylthio)lactam-pyrrolo[2,3-d]n-pyrimidine. The protected 2'(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine and the deprotecting agent are mixed in a suitable solvent, typically an organic solvent, in which both reactants are soluble. Any molar ratio of reactant and deprotecting agent can be used to achieve the desired results. Typically, a large molar excess of the deprotecting reagent is used, eg about 5 equiv. reagent to remove the protective group and about 1.0 equiv. 2'-(Alkylthio)lactam-pyrrolo[2,3-d]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give unprotected 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine. In one non-limiting embodiment, the protected 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine is t-butyl-2'-(methylthio)-6'-oxo-6'H-spiro[cyclohexane-1 ,9'-pyrazino[1,2':1,5]pyrrolo[2,3d]pyrimidine]-7'(8Ή)-carboxylate, the deprotecting agent is hydrochloric acid, the solvent is water, the temperature is about 25°C and the time is about 2 hours.

In one non-limiting embodiment, the 2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine was already unprotected as it was suitable for carrying out the preceding reactions in the absence of a protecting group. Alternatively, the protecting group is left to be removed at a later stage.

The deprotecting agent used in step 6 may be any suitable reagent that allows the deprotection of any suitable protecting group, including, but not limited to, TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzenesulfonic acid, benzoic acid , formic acid, lactic acid, malic acid, malonic acid, methanesulfonic acid, oxalic acid, phthalic acid, salicylic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid , hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, iodic acid, p-hostic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with hydrogen gas, triethylsilane, TBAF, and HF. In one non-limiting embodiment, the protecting group is Boc and the suitable reagent is TFA. In an alternative embodiment, the protecting group is CBz and a suitable reactant is palladium on carbon with hydrogen gas.

The solvent used in step 4 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane and water. In an alternative embodiment, a mixture of solvents is used in step 4. In another alternative embodiment, a deprotecting agent is used as the solvent.

The temperature used in step 4 in non-limiting examples may be from about -20 to about 100°C, from about -10 to about 80°C, from about 0 to about 60°C, from about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 4 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 5: Optional oxidation of 2'-(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine.

In Step 5, 2'-(αkylthio)lactam-pyrrolo[2,3-d]pyrimidine reacts with an oxidant to give 2'-(alkylsulfonyl)lactam-pyrrolo[2,3-d]pyrimidine or 2'-(alkylsulfinyl)lactampyrrolo [2,3-th]pyrimidine. The 2'-(Alkylthio)lactam-pyrrolo[2,3-d]pyrimidine and the oxidizing agent are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants are dissolved. You can use any molar ratio of reactant and oxidant that achieves the desired results. Typically, a large molar excess of the oxidizing agent is used, for example, about 5 equiv. oxidizing agent and about 1.0 equiv. 2'-(alkylthio))-lactampyrrolo[2,3-d]pyrimidine. The reaction can be carried out at any temperature that allows the reaction to take place. The reaction may be continued for a time sufficient to obtain the desired yield of the product, after which the batch is purified by any suitable method, including filtration, crystallization, column chromatography, and to obtain either 2'(alkylsulfonyl)lactam-pyrrolo[2,3-d]pyrimidine , or 2'-(alkylsulfinyl)lactam-pyrrolo[2,3d]pyrimidine. In one non-limiting embodiment, the 2'-(alkylthio)lactam-pyrrolo[2,3d]pyrimidine is 2'-(methylthio)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'pyrazino [1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one, the oxidizing agent is oxone, the solvent is a mixture of water and acetonitrile, the temperature is about 25°C, and the time is about 2 h.

The oxidizing agent used in step 5 can be any suitable reagent that provides oxidation to the sulfone or sulfoxide oxidation state, including, but not limited to, oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite. In one non-limiting embodiment, the product is a sulfone and the oxidizing agent is an oxone.

The solvent used in step 5 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from ACN, water and dioxane. In an alternative embodiment, step 5 uses a mixture of solvents such as water and ACN.

The temperature used in step 5 in non-limiting examples may be from about -20 to about 100°C, from about -10 to about 80°C, from about 0 to about 60°C, from about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 5 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

One skilled in the art will appreciate that the order of the steps prescribed herein may change while achieving the same end product.

In one non-limiting embodiment, the amino lactam is already adequately protected and step 2 does not appear to be necessary. In another embodiment, the selected reagents and starting materials do not need protection to proceed to the desired product, and step 2 and step 4 are not necessary.

In another embodiment, the aminolactam is a compound of formula I, 2(alkylthio)-4-(lactam)pyrimidine-5-carbaldehyde is a compound of formula II, and 2'(alkylthio)lactam-pyrrolo[2,3-d]pyrimidine is is a compound of formula IV.

IIIC. Method for obtaining 1,4-diazaspiro[5.5]undecan-3-ones from cyclohexanone.

It has been found that 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from cyclohexanones. In one non-limiting embodiment, 1,4-diazaspiro[5.5]undecan-3-one is not initially protected and is optionally protected during subsequent synthetic steps.

Stage 1. Obtaining alkyl ( 1 -cyanocyclohexyl) glycinate.

ABOUT

Alkyl

NC NR ²

In step 1, an appropriately substituted alkyl glycinate or salt thereof is reacted with cyclohexanone in the presence of TMSCN to give an alkyl (1-cyanocyclohexyl) glycinate. The cyclohexanone and the alkyl glycinate are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants are dissolved together with a base which will aid the reaction. TMSCN is then slowly added to the mixture. Any molar ratio of the two reactants that achieves the desired results can be used. The reaction can be carried out at any temperature that allows the reaction to take place. Due to the exothermic nature of the reaction, the temperature is controlled on a large scale. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the alkyl (1-cyanocyclohexyl) glycinate. In one non-limiting embodiment, the alkyl glycinate is methyl glycinate or a salt thereof, the base is TEA, the solvent is DCM, the temperature is about 35°C or less, and the time is about 4 hours.

The base used in step 1 may be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine , tripropylamine, tripropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-27 042733 lutidine, morpholine, piperidine , piperazine, proton sponge, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, KH, potassium carbonate, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, TEA,

DBU, DABCO, potassium carbonate and tBuOK. In an alternative embodiment, multiple bases are used in step 1.

The solvent used in step 1 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from TEA, ACN, DCM and DMSO. In an alternative embodiment, step 1 uses a mixture of solvents.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The temperature used in step 1 in non-limiting examples may be from about -20 to about 50°C, from about -10 to about 40°C, from about 0 to about 35°C, or about 10 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 10 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield.

Stage 2. Preparation of 4-diazaspiro[5.5]undecan-3-one.

O

In step 2, the alkyl(1-cyanocyclohexyl)glycinate or salt thereof is reduced with a hydride source and a suitable catalyst and then subjected to intramolecular cyclization to form 4-diazaspiro[5.5]undecan-3-one. The alkyl(1-cyanocyclohexyl)glycinate is dissolved in a suitable solvent. It is then possible to add a reducing agent in the presence of a catalyst to reduce the cyano group to an amine. The amine then acts as a nucleophile in the subsequent intramolecular cyclization to give 4-diazaspiro[5.5]undecan-3-one. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 4-diazaspiro[5.5]undecan-3-one. In one non-limiting embodiment, the alkyl (1-cyanocyclohexyl) glycinate is methyl (1-cyanocyclohexyl) glycinate or a salt thereof, the solvent is methanol, the hydride source is hydrogen gas, the catalyst is platinum oxide, the temperature is about 40°C, and the time is about 3 hours.

The hydride source used in step 2 can be any suitable hydride source, including but not limited to sodium triacetoxyborohydride, hydrogen gas, sodium borohydride, cyanoborohydride, and ammonia formate. In an alternative embodiment, a hydride source is used stoichiometrically without a catalyst, such as sodium triacetoxyborohydride without platinum on carbon.

The solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from methanol, water and ethanol. In an alternative embodiment, a mixture of solvents is used in step 2.

The temperature used in step 2 in non-limiting examples may be from about -10 to about 90°C, from about 0 to about 80°C, from about 10 to about 70°C, from about 20 to about 60°C, or from about 30 to about 50°C. In one non-limiting embodiment, the temperature is selected from about 30 to about 50°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 2 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 o'clock

- 28 042733

Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

IIID. Method for obtaining 1,4-diazaspiro[5.5]undecan-3-one from alkyl-2-oxoacetate.

It has been found that 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from alkyl-2oxoacetate and 1-(aminomethyl)cyclohexane-1-amine, which can optionally be protected. In one non-limiting embodiment, 1,4-diazaspiro[5.5]undecan-3-one is protected, such as t-butyl-3-oxo-1,4-diazaspiro[5.5]undecan-4-carboxylate.

Stage 1. Obtaining alkyl (1- (aminomethyl) cyclohexyl) glycinate.

In step 1, 1-(aminomethyl)cyclohexane-1-amine reacts with alkyl-2-oxoacetate in a reductive amination reaction to give alkyl(1-(aminomethyl)cyclohexyl)glycinate. The 1(aminomethyl)cyclohexane-1-amine and the alkyl-2-oxoacetate are mixed in a suitable solvent, typically a neutral organic solvent, in which both reactants are dissolved, along with a source of catalyst and hydride, which will promote the reductive amination reaction. Any molar ratio of the two reactants that achieves the desired results can be used. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the alkyl (1-(aminomethyl)cyclohexyl)glycinate. In one non-limiting embodiment, 1-(aminomethyl)cyclohexane-1-amine is t-butyl-((1-aminocyclohexyl)methyl)carbamate, alkyl-2-oxoacetate is ethyl-2oxoacetate, catalyst is platinum on carbon, source the hydride is hydrogen gas, the solvent is DCM, the temperature is about 25°C, and the time is about 24 hours.

The hydride source used in step 1 can be any suitable hydride source, including but not limited to sodium triacetoxyborohydride, hydrogen gas, sodium borohydride, cyanoborohydride, and ammonia formate. In an alternative embodiment, a hydride source is used stoichiometrically without a catalyst, such as sodium triacetoxyborohydride without platinum on carbon.

The solvent used in step 1 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyte, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerol, heptane, HMP, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, EtOAc, ethanol, t-butyl alcohol and THF. In an alternative embodiment, step 1 uses a mixture of solvents.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The temperature used in Step 1 in non-limiting examples can be from about -50 to about 50°C, from about -35 to about 40°C, from about -10 to about 30°C, from about -5 to about 20°C. C or from about 0 to about 10°C. In one non-limiting embodiment, the temperature is selected from about 0 to about 10°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 1 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 2: Optional deprotection of alkyl (1-(aminomethyl)cyclohexyl)glycinate.

- 29 042733

In step 2, the alkyl(1-(aminomethyl)cyclohexyl)glycinate is deprotected to give unprotected alkyl(1-(aminomethyl)cyclohexyl)glycinate. The alkyl ( 1 -(aminomethyl)cyclohexyl)glycinate and the deprotecting agent are mixed in a suitable solvent, usually a solvent in which both reactants are soluble. Any molar ratio of reactant and deprotecting agent that achieves the desired results can be used. Typically, a large molar excess of the deprotecting reagent is used, eg about 5 equiv. reagent to remove the protective group and about 1.0 equiv. protected alkyl(1-(aminomethyl)cyclohexyl)glycinate. The reaction can be carried out at any temperature that allows the reaction to take place. Sufficient time is allowed for the reaction to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the deprotected alkyl (1(aminomethyl)cyclohexyl)glycinate. In one non-limiting embodiment, the protected alkyl (1-(aminomethyl)cyclohexyl)glycinate is ethyl (1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)glycinate, the deprotecting agent is hydrochloric acid, the solvent is water, the temperature is about 25°C and the time is about 2 hours.

In one non-limiting embodiment, the alkyl (1 (aminomethyl) cyclohexyl) glycinate has already been deprotected because it was suitable for the previous reaction in the absence of a protecting group. Alternatively, the protecting group is left to be removed at a later stage.

The deprotecting agent used in step 6 may be any suitable reagent that allows the deprotection of any suitable protecting group, including, but not limited to, TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzenesulfonic acid, benzoic acid , formic acid, lactic acid, malic acid, malonic acid, methanesulfonic acid, oxalic acid, phthalic acid, salicylic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid , hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, iodic acid, p-hostic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with hydrogen gas, triethylsilane, TBAF, and HF. In one non-limiting embodiment, the protecting group is Boc and the suitable reagent is TFA. In an alternative embodiment, the protecting group is CBz and a suitable reactant is palladium on carbon with hydrogen gas.

The solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane and water. In an alternative embodiment, a mixture of solvents is used in step 2. In another alternative embodiment, a deprotecting agent is used as the solvent.

The temperature used in step 2 in non-limiting examples may be from about -20 to about 100°C, from about -10 to about 80°C, from about 0 to about 60°C, from about 10 to about 40°C, or from about 20 to about 30°C. In one non-limiting embodiment, the temperature is selected from about 20 to about 30°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 2 for about 1 to about 40 hours, about 3 to about 35 hours, about 5 to about 30 hours, about 10 to about 25 hours, or about 13 to about 20 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Stage 3. Preparation of 4-diazaspiro[5.5]undecan-3-one.

- 30 042733

In step 3, alkyl(1-(aminomethyl)cyclohexyl)glycinate reacts with a base during intramolecular cyclization to form 4-diazaspiro[5.5]undecan-3-ones. The alkyl (1(aminomethyl)cyclohexyl)glycinate and the base are mixed in a suitable solvent, usually a neutral organic solvent, in which both the reactant and the reagent are dissolved. You can use any molar ratio of reactant and reagent that achieves the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 4-diazaspiro[5.5]undecan-3-one. In one non-limiting embodiment, the alkyl (1-(aminomethyl)cyclohexyl)glycinate is ethyl (1-(aminomethyl)cyclohexyl)glycinate, the solvent is THF, the temperature is about 5°C, and the time is about 2 hours.

The base used in step 3 may be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine , tripropylamine, tripropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6lutidine, morpholine, piperidine, piperazine, proton sponge 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, KH, or Trizma. In one non-limiting embodiment, the base is selected from DIPEA, DMAP, DBU, DABCO, TEA, and tBuOK. In an alternative embodiment, multiple bases are used in step 3.

The solvent used in step 3 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water and THF. In an alternative embodiment, a mixture of solvents is used in step 3.

The temperature used in step 3 in non-limiting examples may be from about -50 to about 50°C, from about -35 to about 40°C, from about -10 to about 30°C, from about -5 to about 20° C or from about 0 to about 10°C. In one non-limiting embodiment, the temperature is selected from about 0 to about 10°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

IIID. An alternative method for the preparation of 1,4-diazaspiro[5.5]undecan-3-ones from cyclohexanone.

In a further embodiment, 1,4-diazaspiro[5.5]undecan-3-ones can be prepared from cyclohexanone using a cyano intermediate.

Stage 1. Obtaining 1-aminocycloalkyl-1-carbonitrile.

In step 1, the cyclic ketone is reacted with a source of cyanide and ammonia, and optionally with additional reagents or catalysts, to form 1-aminocycloalkyl-1carbonitrile. The cyclic ketone, source of cyanide, and source of ammonia are mixed in a suitable solvent, usually a neutral organic solvent, in which both reactants are soluble. You can use any molar ratio of the two reactants, which allows you to achieve the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. Reactions allow enough time to ensure

- 31 042733 the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to obtain 1-aminocycloalkyl-1-carbonitrile. In one non-limiting embodiment, the cyclic ketone is cyclohexanone, the cyanide source is TMSCN, the ammonia source is ammonia, the 1-aminocycloalkyl-1-carbonitrile is 1-(aminomethyl)cyclohexane-1-amine, and the catalyst is titanium isopropoxide. In one embodiment, centrifugation is used to isolate 1-aminocyclylalkyl-1-carbonitrile. In another embodiment, Celite filtration is used to isolate the 1-aminocyclylalkyl-1-carbonitrile.

The solvent used in step 1 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyte, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerol, heptane, HMP, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, EtOAc, ethanol, t-butyl alcohol and THF. In an alternative embodiment, a mixture of solvents is used. In one embodiment, no solvent is used.

In an additional embodiment, the solvent used in step 1 is dioxane. In another additional embodiment, the solvent is selected from DCM, EtOAc, ethanol, dioxane, t-butyl alcohol and THF.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 1 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Stage 2. Obtaining 1-(aminomethyl) cycloalkyl-1-amine.

In Step 2, 1-aminocycloalkyl-1-carbonitrile is reduced to give 1(aminomethyl)cycloalkyl-1-amine. The 1-aminocycloalkyl-1-carbonitrile and the reducing agent are mixed in a suitable solvent, usually a solvent in which both reactants are soluble. You can use any molar ratio of reactant and reducing agent that achieves the desired results. Typically, a molar excess of the reducing agent is used, eg about 2 equiv. recovery reagent and about 1.0 equiv. 1-aminocycloalkyl-1-carbonitrile. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 1-(aminomethyl)cycloalkyl-1-amine. In one non-limiting embodiment, 1-aminocycloalkyl-1-carbonitrile is 1(aminomethyl)cyclohexane-1-amine, the reducing agent is lithium aluminum hydride (LAH), the temperature is about 45°C, and the time is about 30 minutes.

The reducing reagent used in step 2 can be any suitable reagent that allows the reduction of the cyano group, including, but not limited to, LAH, BH3-THF, BH ₃ SMe ₃ , H ₂ , H2 with Raney nickel, and H with Pd/ C.

The solvent used in step 2 can be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane and water. In an alternative embodiment, a mixture of solvents is used in step 2.

The temperature used in step 2 in non-limiting examples may be from about -20 to about 100°C, from about -10 to about 90°C, from about 0 to about 80°C, from about 10 to about 70°C, or from about 20 to about 60°C. In one non-limiting embodiment, the temperature is selected from about 30 to about 50°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in step 2 for about 10 minutes to about 3 hours, from

- 32 042733 about 10 minutes to about 2 hours, about 10 minutes to about 1 hour, about 10 minutes to about 50 minutes, or about 20 minutes to about 40 minutes. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Stage 3. Obtaining a protected 1-(aminomethyl)cycloalkyl-1-amine.

PG I

In step 3, 1-(aminomethyl)cycloalkyl-1-amine is reacted with a protecting group reagent to form a protected 1-(aminomethyl)cycloalkyl-1-amine. The 1-(aminomethyl)cycloalkyl-1-amine and the protecting group reagent are mixed in a suitable solvent, typically a neutral organic solvent in which both reactants are dissolved along with a base which will facilitate the introduction of the protecting group. Any molar ratio of the two reactants that achieves the desired results can be used. Typically, a molar deficit or equivalent of the protecting group reagent is used, eg, about 0.6, 0.7, 0.8, 0.9, 1, or 1.1 equiv. protecting group reagent and about 1 equiv. 1-(aminomethyl)cycloalkyl-1-amine. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the protected 1(aminomethyl)cycloalkyl-1-amine. In one non-limiting embodiment, 1(aminomethyl)cycloalkyl-1-amine is 1-(aminomethyl)cyclohexane-1-amine, the protecting group reagent is Boc anhydride, the protected 1-(aminomethyl)cycloalkyl-1-amine is tert -butyl-((1-aminocyclohexyl)methyl)carbamate, no base is used, and the temperature is about -70°C.

The protecting group reagent used in step 3 can be any suitable reagent that allows any suitable protecting group to be established, including but not limited to Boc anhydride, Boc-Cl, CBz-Cl, methyl chloroformate, benzyl chloride, benzoyl chloride, allyl chloride, triflic anhydride, Tf-Cl, tosyl anhydride and Ts-Cl. In one non-limiting embodiment, the protecting group is Boc and a suitable reagent is either Boc anhydride or Boc-Cl. In an alternative embodiment, the protecting group is CBz and the suitable reagent is CBz-Cl.

In one embodiment, step 3 is carried out without the addition of a base. If a base is used, it can be any suitable organic base including, but not limited to, DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, tripropylamine , triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6-lutidine, morpholine, piperaid-spon 1, 5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine and Trizma.

The solvent used in step 3 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, dioxane, water and THF. In an alternative embodiment, a mixture of solvents is used in step 3.

The temperature used in step 3 in non-limiting examples may be from about -100 to about 20°C, from about -90 to about 0°C, from about -80 to about -10°C, from about -80 to about - 40°C or from about -80 to about -60°C. In one non-limiting embodiment, the temperature is selected from about -80 to about -60°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 3 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 4 hours. Those skilled in the art will recognize that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, more reaction time will be required to obtain the desired yield, but less may be present.

- 33 042733 by-products.

Step 4. Obtaining alkyl (1- (((protecting group) amino) methyl) cyclo-alkyl) glycinate. alkyl

In step 4, the protected 1-(aminomethyl)cycloalkyl-1-amine is reacted with a base and alkyl-2-bromoacetate to form alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate. The protected 1-(aminomethyl)cycloalkyl-1-amine and the base are mixed in a suitable solvent, typically a neutral organic solvent, in which both the reactant and the reagent are dissolved. You can use any molar ratio of reactant and reagent that achieves the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give the alkyl (1-(((protecting group) amino) methyl) cycloalkyl) glycinate. In one non-limiting embodiment, the protected 1-(aminomethyl)cycloalkyl-1-amine is t-butyl-((1aminocyclohexyl)methyl)carbamate, the solvent is acetonitrile, the base is K ₂ CO ₃ , and alkyl(1-(( (protecting group)amino)methyl)cycloalkyl)glycinate is methyl-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)glycinate.

The base used in step 4 may be any suitable base, including but not limited to DIPEA, DMAP, DBU, TEA, pyridine, ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine , tripropylamine, triisopropylamine, aniline, methylaniline, dimethylaniline, pyridine, azajulolidine, benzylamine, methylbenzylamine, dimethylbenzylamine, DABCO, 1,5-diazabicyclo[4.3.0]non-5-ene, 2,6lutidine, morpholine, piperidine, piperazine, proton sponge 1,5,7-triazabicyclo[4.4.0]dec-5-ene, tripelennamine, ammonium hydroxide, triethanolamine, ethanolamine, NaOH, tBuOK, NaH, KH, or Trizma. In one non-limiting embodiment, the base is selected from K ₂ CO ₃ , Na ₂ CO ₃ and MgCO ₃ . In an alternative embodiment, multiple bases are used in step 4.

The solvent used in step 4 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from acetonitrile, dioxane, water and THF. In an alternative embodiment, a mixture of solvents is used in step 4.

The temperature used in step 3 in non-limiting examples may be from about 0 to about 100°C, from about 0 to about 90°C, from about 0 to about 80°C, from about 20 to about 80°C, or from about 30 to about 80°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 4 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

Step 5. Preparation of 4-diazaspiro[5.5]undecan-3-one.

In Step 5, the alkyl (1-(((protecting group) amino) methyl) cycloalkyl) glycinate is deprotected with a deprotecting agent and then treated with acid to induce intramolecular cyclization to give 4-diazaspiro[5.5]undecane-3one. The alkyl (1-(((protecting group)amino)methyl)cycloalkyl)glycinate and the deprotecting agent are mixed in a suitable solvent, usually a solvent in which both the reactant and the reagent are dissolved. Any molar ratio of reactant to reagent can be used, as long as

- 34 042733 which achieves the desired results. The reaction can be carried out at any temperature that allows the reaction to take place. The reactions are allowed sufficient time to provide the desired yield, after which the batch is purified by any suitable method, including filtration, crystallization and column chromatography, to give 4-diazaspiro[5.5]undecan-3-one. In one non-limiting embodiment, the alkyl (1-(((protecting group) amino) methyl) cycloalkyl) glycinate is methyl (1- (((tert-butoxycarbonyl) amino) methyl) cyclohexyl) glycinate, the solvent is DCE, the acid is TFA , the deprotecting agent is TFA, the temperature reaches approximately boiling point, and 4-diazaspiro[5.5]undecan-3-one is 1,4-diazaspiro[5.5]undecan-3-one.

The deprotecting agent used in step 6 may be any suitable reagent that allows the deprotection of any suitable protecting group, including, but not limited to, TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzenesulfonic acid, benzoic acid , formic acid, lactic acid, malic acid, malonic acid, methanesulfonic acid, oxalic acid, phthalic acid, salicylic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid , hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, iodic acid, p-hostic acid, phosphoric acid, palladium on carbon with or without hydrogen gas, platinum on carbon with hydrogen gas, triethylsilane, TBAF, and HF. In one non-limiting embodiment, the protecting group is Boc and the suitable reagent is TFA. In an alternative embodiment, the protecting group is CBz and a suitable reactant is palladium on carbon with hydrogen gas.

The acid used in step 5 can be any suitable acid that provides intramolecular cyclization, including but not limited to TFA, acetic acid, aminomethanesulfonic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, formic acid, lactic acid, malic malonic acid, methanesulfonic acid, oxalic acid, phthalic acid, salicylic acid, succinic acid, sulfamic acid, p-toluenesulfonic acid, trichloroacetic acid, trifluoromethanesulfonic acid, boric acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, iodic acid, nitric acid, perchloric acid, iodic acid, phosphinic acid and phosphoric acid. In one non-limiting embodiment, the acid is TFA.

The solvent used in step 5 may be any suitable organic solvent, including but not limited to DMAc, DCM, THF, DMF, TFA, ACN, DMAP, water, acetic acid, acetone, dioxane, benzene, 1-butanol , 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, DME, DMSO, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, HMPA, methanol, MTBE, NMP, pentane, pyridine, toluene, hydrochloric acid and triethylamine. In one non-limiting embodiment, the solvent is selected from DCM, DCE, TFA and TFIF. In an alternative embodiment, a mixture of solvents is used in step 5.

The temperature used in step 5 in non-limiting examples may be from about 30 to about 100°C, from about 35 to about 90°C, from about 50 to about 85°C, from about 55 to about 85°C, or from about 60 to about 85°C.

The reaction can be carried out for a time sufficient to obtain the desired product yield. For example, the reaction may continue in Step 5 for about 0.1 to about 20 hours, about 0.5 to about 15 hours, about 1 to about 10 hours, about 1.5 to about 5 hours, or about 2 to about 3 hours. Those skilled in the art will appreciate that reaction time and temperature are interrelated. For example, if a higher temperature is used, a lower reaction time may provide the desired yield. Alternatively, if a lower temperature is used, a longer reaction time will be required to obtain the desired yield, but fewer by-products may be present.

In one embodiment, 4-diazaspiro[5.5]undecan-3-one is isolated as a salt. In another embodiment, 4-diazaspiro[5.5]undecan-3-one is isolated as the free base.

In one embodiment, the 4-diazaspiro[5.5]undecan-3-one salt is dissolved or suspended in a solvent and then exposed to a base. In one embodiment, the solvent is ethanol. In one embodiment, the solvent is DCM. In one embodiment, the base is K2CO3. In one embodiment, the solvent is ethanol and the base is K2CO3. In one embodiment, the solvent is DCM and the base is K2CO3.

IV. New intermediates.

- 35 042733

In one non-limiting embodiment, a number of compounds used in the production process described herein are new. Some of them are described below.

In one embodiment, a compound of formula II is provided

as well as its salts. Formula II is heteroaryl linked to a spirocyclic lactam.

Non-limiting examples of compounds falling under formula II are illustrated below. The present disclosure includes all combinations of these definitions as long as a stable compound is obtained.

In one aspect, the present disclosure includes compounds and salts of formula IIA

where R ⁵ is as defined herein. Non-limiting examples of R ⁵ are hydrogen, bromine, chlorine, fluorine, iodine, -CF3, -OEt, -OMe, -NCH ₃ OMe and -OC(O)CH ₃ .

In one aspect, the present disclosure includes compounds and salts of formula IIB

where R ² is as defined herein.

Non-limiting examples of R ² are hydrogen, -Boc, -CBz, -Bn, methyl carbamate and methyl.

In one aspect, the present disclosure includes compounds and salts of formula IIC

where R ¹ is as defined herein. Non-limiting examples of R ¹ are methyl, -CF3, -Bn, -Ph, -Et, propyl, and isopropyl.

In one aspect, the present disclosure includes compounds and salts of formula IID

- 36 042733 where R ¹ is as defined in this document. Non-limiting examples of R ¹ are methyl, -CF ₃ , -Bn, -Ph, -Et, propyl and isopropyl.

Non-limiting examples of compounds that can be synthesized by methods

set in the present invention include:

- 37 042733

- 38 042733

V. Illustrative examples.

According to the present invention, there is provided a process for preparing compounds of formula I, formula II, formula III or formula IV:

as well as their salts. In one non-limiting embodiment, the compounds of the above formulas are used in the synthesis of CDK inhibitors.

- 39 042733

Abbreviations.

ACN Acetonitrile AUC Area under the curve Vos tert-butyloxycarbonyl Vos ₂ O di-tert-butyl dicarbonate CBZ carboxybenzyl DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8 Diazabicycloundec-7-ene DCM, CH ₂ C1 dichloromethane DIEA, DIPEA Ν,Ν-diisopropylethylamine DMA, DMAc Ν,Ν-dimethylacetamide DMAP 4-dimethylaminopyridine DMF Ν,Ν-dimethylformamide DMSO Dimethyl sulfoxide Et Ethyl 4, 4 Hour, clock HMPA Hexamethylphosphoramide HPLC High-dag liquid chromatography _{K2CO3 _} Potassium carbonate mCPBA meta-chloroperoxybenzoic acid MTBE Methyl tertiary butyl ether NMP №Methyl-2-pyrrolidone NMR Nuclear magnetic resonance Pd(PPh ₃ ) ₄ Tetrakis (triphenylphosphine)palladium(O) Pt Platinum RT Room temperature TEA Trimethylamine _Tf2O Trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF Tetrahydrofuran

General ways.

The structure of the starting materials, intermediates and final products was confirmed by standard analytical methods, including NMR spectroscopy and mass spectrometry. Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE 500 at 500 MHz in DMSO-d6. HPLC analysis was performed on HPLC Waters using the HPLC method below.

HPLC method.

Column:

Column temperature:

Flow rate:

Atlantis TK (150 * 4.6, 3 µm) °C ml/min

Detection:

Analysis time: Mobile phase A: Mobile phase B: Sample preparation:

UV @ 275 nm min

Water (with 0.1% trifluoroacetic acid)

Acetonitrile (with 0.1% trifluoroacetic acid) dissolve ion pair chromatography (IPC) sample, wet or dry solid (~1 mg active compound) in acetonitrile/water (1/1) until complete dissolution is achieved .

Gradient HPLC method.

Time (Minutes) % A % V 0 100 0 5 100 0 23 5 95 28 5 95 28.1 100 0

- 40 042733

Example 1 General synthetic routes.

Scheme 1-1.

Scheme 1-1. Starting from an appropriately substituted halopyrimidine, the compounds of the present invention can be prepared. In Step 1, an appropriately substituted halopyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one, in the presence of a base and with heat, to give the substituted spirolactam. In step 2, an appropriately substituted spirolactam is protected by a group selected from R ² . In step 3, the protected spirolactam is cyclized in the presence of a base to form a fused spirolactam. The condensed spirolactam may optionally be oxidized to a sulfoxide or sulfone after step 3, step 4, step 5, or step 6. Oxidation before step 3 results in undesirable by-products. In step 4, the hydroxyl group of the fused spirolactam is converted to a leaving group. In step 5, the leaving group is dehydrated to give a compound of formula IV. In step 6, the compound of formula IV is optionally deprotected.

Scheme 1-2.

Scheme 1-2. Starting from an appropriately substituted halopyrimidine, the compounds of the present invention can be prepared. In Step 1, an appropriately substituted halopyrimidine is subjected to 1,4-diazaspiro[5.5]undecan-3-one, in the presence of a base and with heat, to give the substituted spirolactam. In step 2, an appropriately substituted spirolactam is protected by a group selected from R ² . In step 3, the protected spirolactam is cyclized in the presence of a base to give the fused spirolactam of formula IV. The condensed spirolactam may optionally be oxidized to a sulfoxide or sulfone after step 3 or step 4. Oxidation before step 3 results in undesirable by-products. In step 4, the compound of formula IV is optionally deprotected. Scheme 1-3.

Scheme 1-3. Starting from an appropriately substituted alkyl glycinate, the compounds of the present invention can be prepared. In step 1, an appropriately substituted alkyl glycinate is reacted with cyclohexanone and TMSCN in the presence of a base to give the cyano derivative. In step 2, the suitably substituted cyano derivative is reduced and then cyclized to give the compound of formula I.

- 41 042733

Scheme 1-4.

Scheme 1-4. Starting from an appropriately substituted 1-(aminomethyl)cyclohexane-1-amine, the compounds of the present invention can be prepared. In step 1, an appropriately substituted 1-(aminomethyl)cyclohexane-1-amine is reductively aminated with an aldehyde. In step 2, the suitably substituted cyclohexanamine is optionally deprotected (ie: a group selected from R ² if not H, optionally replaced by H). In step 3, cyclohexanamine is acylated to give a compound of formula I. In step 4, a compound of formula I is optionally protected.

Scheme 1-5.

Scheme 1-5. Starting from an appropriately substituted halopyrimidine, the compounds of the present invention can be prepared. In Step 1, an appropriately substituted halopyrimidine is treated with 1,4-diazaspiro[5.5]undecan-3-one, in the presence of a base and with heat, to give the substituted spirolactam. In step 2, the protected spirolactam is cyclized in the presence of a base to form a condensed spirolactam.

The condensed spirolactam may optionally be oxidized to a sulfoxide or sulfone after step 2, step 3, step 4, or step 5. Oxidation before step 2 results in undesirable by-products. In step 3, the hydroxyl group of the fused spirolactam is converted to a leaving group. In step 4, the leaving group is dehydrated to give a compound of formula IV. In step 5, the compound of formula IV is optionally deprotected.

Scheme 1-6.

Scheme 1-6. Starting from an appropriately substituted halopyrimidine, the compounds of the present invention can be prepared. In step 1, an appropriately substituted halopyrimidine is exposed to 1,4-diazaspiro[5.5]undecan-3-one, in the presence of a base

- 42 042733 and when heated, to obtain a substituted spirolactam. In step 2, the protected spirolactam is cyclized in the presence of a base to give the fused spirolactam of formula IV. The condensed spirolactam may optionally be oxidized to a sulfoxide or sulfone after step or step 3. Oxidation before step 2 results in undesirable by-products. In step 3, the compound of formula IV is optionally deprotected.

Scheme 1-7.

Scheme 1-7. Starting from a compound of formula IV, a CDK4/6 inhibitor can be obtained. In Step 1, a heteroaryl amine is attacked with a base and a compound of formula IV is slowly added under cooling conditions to give a nucleophilic substitution reaction. The compound of formula IV can be pre-prepared as described in the schemes herein.

Example 2 Exemplary synthetic routes.

Scheme 2-1.

Scheme 2-1. The ester route is one embodiment of the present invention. Ideally, a better synthesis scheme would allow the preparation of crystalline intermediates to provide material of adequate purity without column chromatography and a high yield step using safe and cost effective reagents whenever possible.

The first step in the ester synthetic route is the nucleophilic substitution of the SNAr group of Cl in the commercially available ester 3 using spirolactam 4. Due to the low reactivity of 4, a reaction temperature of 85 to 95°C was required. Due to temperature requirements, DIPEA and dimethylacetamide were chosen as the base and solvent, respectively. The reaction follows second order kinetics and usually stops after ~85% conversion. Therefore, the reaction was usually stopped after 60 hours by first cooling the reaction mixture to room temperature, after which the formation of a solid was observed. The mixture was then subjected to distribution in the MTBE/water system and the product was filtered, achieving an excellent degree of purification with ~ 53% yield of the desired product 5. The resulting compound 5 was protected with a Boc group using Boc anhydride and DMAP as a catalyst and dichloromethane as a solvent . Intermediate 6 was obtained in quantitative yield. Due to the semi-solid nature of compound 6, the material entered the next step without further purification. The Dieckmann condensation was originally performed with strong bases such as LiHMDS and tert-BuOK. A result similar to the aldehyde route (Scheme 2-2) was obtained: partial removal of the Boc protecting group was observed, which required column chromatography. However, the best results were

- 43 042733 obtained using DBU as a base and THF as a solvent. As a result, the reaction was completely completed, with clear conversion of compound 6 to compound 7. In addition, the product crystallized from the reaction mixture after seeding, and a quantitative yield was obtained for two steps.

The hydroxyl group 7 was removed using a two-step procedure. First, compound 7 was completely converted to triflate 8 using triflic anhydride and triethylamine in dichloromethane. The reaction was found to proceed well at 0°C. Due to the potential instability of the triflate intermediate, it was not isolated. It was immediately taken to the next step and reduced with triethylsilane and palladium tetrakis to give product 9 after crystallization of ethyl acetate in ~70% yield. The Boc group from 9 was removed with trifluoroacetic acid in dichloromethane to give 10. Intermediate 10 was converted to the final sulfone 11 using Oxone™ in an acetonitrile/water solvent system.

The resulting sulfone 11 was tested prior to use in the coupling step and found to work well. Finally, a route to sulfone 11 was developed that eliminated the use of column chromatography, with good to excellent yields at all stages.

Scheme 2-2.

Scheme 2-2. The first step of Scheme 2-2 consistently gave product 13 contaminated with one major impurity found in significant amounts. A thorough evaluation of the impurity reaction profile by LC-MS and 2D NMR was carried out, which showed that the impurity is structurally a condensation of two aldehyde 12 molecules and one lactam 4 molecule. yield 30%. Solvent screening indicated that sec-butanol, amyl alcohol, dioxane and tert-butanol could be used in the reaction, but similar conversion was observed in each case. However, tert-butanol provided the purest reaction profile, so it was chosen as the solvent for the reaction. Also investigated the evaluation of the influence of varying the stoichiometric ratio of 4 and 12 on the result of the reaction. The reaction was carried out with 4 equivalents of amine 4 in an attempt to destroy the 2:1 aldehyde/amine impurity. The result was only a slight increase in the formation of product 13. Next, the effect of temperature on the reaction result was evaluated. The binding of aldehyde 12 and 4 was studied at two different temperatures: 50 and 40°C, with an aldehyde/amine ratio of 1:1. Reactions were checked after 2 and 4 hours, and then every 12 hours. The reaction proceeded slowly at 50°C and was accompanied by an increase in the content of other impurities. The reaction at 40°C was much cleaner; however, the conversion rate was lower over the same time period. The method of adding reagents was also investigated at 80°C, with slow (over 6 h) addition of either aldehyde 12 or amine 4 to the reaction mixture. The product distribution did not change and a ratio of about 1 to 1 was observed between product and impurity when amine 4 was slowly added to the reaction mixture containing aldehyde 12 and DIPEA under reflux. The product distribution changed when aldehyde 12 was slowly added to the mixture of amine 4 and DIPEA. However, the main product of the reaction was an unwanted impurity. Other organic bases have been tried, as well as different ratios of DIPEA. No product was observed when potassium carbonate was used as the base. The results of the experiments are presented in table. 1 below.

- 44 042733

Table 1

Sequence number Base Product (AUC%, 270 nm) Impurity 22.3 min (AUC%, 270 nm) 1 TEA 55 45 2 DABCO No No 3 4 5 6 DBU pyridine 2,6-lutidine DIPEA 2 eq. No No 35 55 No No 65 40 7 DIPEA 3 eq. 46 49 8 DMAP No No

Compound 13 was successfully formed in three cases: triethylamine, 2,6-lutidine and DIPEA, and the result obtained with DIPEA was the best. The use of Boc-protected spirolactam 4 also did not affect the formation of impurities. It was used on the assumption that its use would be advantageous in performing the coupling step together with the next step, obtaining compound 14.

The main impurity formed in stage 1 of Scheme 2-2 is

SMe

MeS

Chemical Foomula: la: C2iH ₂₄ Cl ₂ N ₆ O ₂ S2

Molecular weight: it: 527.4903

The second step (Boc-protection of the free lactam) proceeded well using DMAP as a catalyst in dichloromethane at room temperature. Product 14 is a thick oil and therefore cannot be purified by crystallization. The Boc-protected intermediate 14 was successfully cyclized to the desired pentacyclic structure 10 after treatment with a strong base such as LiHMDS or t-BuOK. Surprisingly, the Boc group was partially removed during the reaction. The level of deprotection was independent of the temperature inside the reaction mixture and positively correlated with the excess base used. Therefore, the mixture of target product 10 and compound 10-Boc was treated with acid to completely remove the Boc protecting group. The conversion of methyl sulfide to the final sulfone 11 was carried out using Okope™. First, a mixture of methanol and water was used for the reaction. As a result, partial displacement of the sulfone by the methoxy group was found. The methanol was replaced with acetonitrile and the displacement of the sulfone was eliminated.

Thus, the ester route (Scheme 2-1) is preferred because:

1) impurity formation during the first step of Scheme 2-2 was unavoidable and ultimately resulted in <35% yields;

2) purification on a column was required to isolate intermediate 14;

3) the starting aldehyde material was not commercially available and required two synthetic steps from the corresponding ester.

Scheme 2-3.

H N^V' ⁰ ' ⁴ ' ^{TEM 2} ' D + TMSCN DCM

HCI

Stage 1

Ryu ₂ , N ₂

Meon

HN

Stage 2

Scheme 2-3. Starting with cyclohexanone, the compounds of the present invention can be obtained. In step 1, methyl glycinate is subjected to cyclohexanone and TMSCN in the presence of triethylamine in DCM to give 15. In step 2, compound 15 is hydrogenated with hydrogen gas in

- 45 042733 the presence of catalytic platinum oxide and then subjected to intramolecular cyclization to obtain compound 16, which is used in the schemes above.

Scheme 2-4.

Scheme 2-4. Starting from compound 17, the compounds of the present invention can be obtained. In step 1, compound 17 is treated with ethyl 2-oxoacetate in the presence of platinum on carbon and hydrogen gas to give compound 18. In step 2, compound 18 is deprotected with Boc-protective group with hydrochloric acid. In step 3, compound 18 is cyclized to give compound 16, which is used in the schemes above.

Scheme 2-5.

Scheme 2-5. Starting from compound 11, a CDK 4/6 inhibitor 19 can be prepared. In step 1, 5-(4methylpiperazin-1-yl)pyridin-2-amine is exposed to LiHMDS and compound 11 is slowly added under cooling conditions to give a nucleophilic substitution reaction and compound 19 Compound 11 can be prepared as described in the schemes provided herein.

Diagram 2-6

Scheme 2-6. Starting from compound 11, a CDK 4/6 inhibitor 20 can be prepared. In Step 1, 5-(4isopropylpiperazin-1-yl)pyridin-2-amine is exposed to LiHMDS and compound 11 is slowly added under cooling conditions to give a nucleophilic substitution reaction and compound 20. Compound 11 can be prepared as described in the schemes provided herein.

Get connection 5.

Ethyl 4-chloro-2(methylthio)pyrimidine-5-carboxylate 3 (49.2 g, 0.21 mol , 1.00 equiv.), spirolactam 4 (39.2 g, 0.23 mol, 1.10 equiv.), DIPEA (54.7 g, 0.42 mol, 2.00 equiv.), and DMAc (147 .6 ml, 3 volumes). The reaction mixture was heated to 90 to 95° C. and after 60 h ion pair chromatography confirmed that ~14% (AUC) of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate remained. The reaction mixture was cooled to RT and the formation of a precipitate was observed. The suspension was diluted with MTBE (100 ml, 2 vols) and water (442 ml, 9 vols) and stirred for 2 h at RT. The product was isolated by vacuum filtration and washed with MTBE (49 ml, 1 vol). The solid was conditioned for 1 hour and dried in vacuo at 40° C. for 16 hours to give Compound 5 [41.0 g, 53% yield] as an off-white solid with >99% AUC purity. ¹ H-NMR (CDCl ₃ ): δ 8.76 (d, J=2.0 Hz, 1H), 6.51-6.29 (br, 1H), 4.33 (q, J=7.0 Hz, 2H), 3.78 (s, 2H), 3.58 (s, 2H), 2.92 (s, 2H), 2.53 (s, 3H), 1.63-1.37 (m , 12H). LCMS (ESI, m/z=365.3 [M+H]).

Getting connection 6.

into a 500 ml three-necked flask equipped with an overhead mechanical stirrer, thermocouple and

- 46 042733 N2 inlet, loaded with 5 [41.0 g, 0.11 mol, 1.00 equiv], Boc anhydride (36.8 g, 0.17 mol, 1.50 equiv), DMAP (1.37 g, 0.01 mol, 0.10 equiv) and dichloromethane (287 ml, 7 vols). The reaction mixture was stirred for 3 h at RT. Ion pair chromatography confirmed that no starting materials remained (AUC). The reaction mixture was concentrated to a residue under reduced pressure and carried on to the next step (a quantitative yield was assumed for this step). An aliquot (200 mg) was purified by column chromatography (heptanes/ethyl acetate 0 to 100%) to give compound 6. ¹ H-NMR (CDCl ₃ ): δ 8.64 (s, 1H), 4.31 (q, J= 7.0 Hz, 2H), 4.07 (s, 2H), 3.83 (S, 2H), 3.15 (m, 2H), 2.56. (s, 3H), 172 (m, 3H), 1.59 (m, 15H), 1.42 (t, J=7.0 Hz, 3H). LCMS (ESI, m/z=465.2 [M+H]).

Getting connection 7.

A 500 ml three-necked flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet was charged with Compound 6 [residue from the previous step, estimated quantitative yield 52.2 g, 0.11 mol, 1.00 equiv.] and THF (261 ml, 5 volumes). The mixture was cooled to 0°C and 1,8-diazabicyclo[5.4.0]un-dec-7-ene (17.1 g, 0.11 mmol, 1.00 equiv.) was added, maintaining the temperature within the reaction mixture in the range from 0 to 10°С. After the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature, and after 2 hours ion pair chromatography confirmed that no starting material remained. The reaction mixture was added seed product (1.0 g) and cooled to 0°C. The suspension was stirred at 0° C. for 2 hours. The product was isolated by vacuum filtration and washed with cold (0° C.) THF (50 ml, 1 vol). The solid was conditioned for 1 hour and dried in vacuo at 40° C. for 16 hours to give 7 [47 g, quantitative yield] as a light orange solid with >99% AUC purity. The color of the product changed to yellow after the batch was exposed to air for an extended period of time (~1 day). The material was isolated in a significant amount of DBU, according to proton NMR. However, this did not prevent the next stage. ¹ H-NMR (CDCl ₃ ): δ 8.71 (s, 1H), 4.03 (s, 2H), 2.57 (s, 3H), 1.85 (m, 10H), 1.51 ( s, 9H). LCMS (ESI, m/z=419.2 [M+H]).

Getting connection 8.

A 500 mL three-neck flask equipped with an overhead mechanical stirrer, thermocouple, and N2 inlet was charged with 7 [40.8 g, 0.10 mol, 1.00 equiv.], triethylamine (31.5 g, 0.31 mol, 3.20 equiv.) and dichloromethane (408 ml, 10 volumes). The reaction mixture was purged with N2 for 15 min and cooled to 0°C. Triflic anhydride (44.0 g, 0.16 mol, 1.60 equiv.) was added while maintaining the temperature inside the reaction mixture in the range of 0 to 10°C. The reaction mixture was stirred at 0° C. and after 3 h ion pair chromatography confirmed that 7.0% (AUC) of compound 7 remained. When complete, the reaction mixture was transferred to a 1 L separating funnel and washed with 50% saturated sodium bicarbonate (200 mL, 5 vols). [It was prepared by mixing saturated sodium bicarbonate (100 ml) with water (100 ml).] The aqueous layer was separated and extracted with DCM (2x40 ml, 1 vol). The organic layers were combined and concentrated to a residue under reduced pressure and carried on to the next step. LCMS (ESI, m/z=551.6 [M+H]).

Getting connection 9.

A 500 ml three-necked flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet was charged with Compound 8 [residue from the previous step, estimated quantitative yield, 53.7 g, 0.10 mol, 1.00 equiv.] and THF (110 ml, 2 volumes). The solvent was removed by vacuum distillation and the procedure was repeated twice. The flask was charged with triethylsilane (22.7 g, 0.20 mol, 2.00 equiv.) and DMF (268 ml, 5 vols). The reaction mixture was degassed with five cycles of evacuation followed by filling with nitrogen. The flask was charged with tetrakis(triphenylphosphine)palladium(0) (11.3 g, 0.01 mol, 0.1 equiv.). The reaction mixture was heated to 4550° C. and after 14 h ion pair chromatography confirmed that no starting material remained. The reaction mixture was transferred to a 500 ml separating funnel while still warm. The reaction mixture was partitioned between water (5 volumes) and ethyl acetate (5 volumes). The aqueous layer was extracted with ethyl acetate (3x3 volumes). The organic layers were combined and concentrated to 2 volumes. The precipitate was filtered off and washed with ethyl acetate (2x1 volume). The solid was conditioned for 1 hour and dried in vacuo at 40° C. for 16 hours to give 9 [27.5 g, 70% yield] as a yellow solid with ~98% AUC purity. Proton NMR indicated the presence of some triphenylphosphine oxide. ¹ H-NMR (DMSO-d ₆ ): δ 9.01 (s, 1H), 7.40 (s, 1H), 4.30 (s, 2H), 2.58 (m, 2H), 2, 58 (s, 3H), 1.81 (m, 5H), 1.51 (s, 9H). LCMS (ESI, m/z=403.4 [M+H]).

Obtaining compound 10 according to scheme 2-1.

A 500 ml three-necked flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet was charged with 9 (12.8 g, 31.8 mmol, 1.00 equiv.) and dichloromethane (64 ml, 5 vols). Trifluoroacetic acid (18.2 g, 159 mmol, 5.00 equiv.) was added over 20 minutes and the solution was stirred for 2 hours at RT. Ion pair chromatography confirmed that the reaction was complete. The reaction mixture was transferred to a 500 ml separating funnel and washed with saturated sodium bicarbonate (200 ml). The aqueous layer was extracted with dichloromethane (3x3 volumes).

- 47 042733

The organic layers were combined and concentrated to 1 volume. The precipitate was filtered off and conditioned for 1 hour and dried in vacuo at 40° C. for 16 hours to give 9 [6.72 g, 70% yield] as an off-white solid with a purity of 99.1% AUC. ¹ H-NMR (DMSO-d ₆ ): δ 8.95 (s, 1H), 8.32 (s, 1H),

7.15 (s, 1H), 3.68 (d, J=1.0 Hz, 2H), 2.86 (m, 2H) 2.57 (s, 3H), 1.92 (m, 2H) , 1.73 (m, 3H), 1.39 (m, 3H). LCMS,

ESI, m/z=303.2 [M+H]).

Obtaining compound 10 according to scheme 2-2.

14 (680 mg, 1.62 mmol, 1.00 equiv.) and THF (6.8 ml, 10 volumes) were charged to a 50 ml three-necked flask equipped with a magnetic stirrer, thermocouple, N2 inlet. A 1 M solution of potassium tert-butoxide (3.2 ml, 3.24 mmol, 2.00 equiv.) in THF was added over 10 minutes and the solution was stirred for 2 hours at RT. Ion pair chromatography confirmed that the reaction was complete. The reaction mixture was acidified with 4N. a solution of hydrogen chloride in dioxane (2.4 ml, 9.72 mmol, 6.00 equiv.) and stirred for an additional 1 hour. The reaction mixture was transferred to a 500 ml separating funnel and washed with saturated sodium bicarbonate (100 ml). The aqueous layer was extracted with ethyl acetate (3x20 volumes). The organic layers were combined and concentrated to 3 volumes and the product precipitated out. The precipitate was filtered off and conditioned for 1 h and dried in vacuo at 40° C. for 16 h to give 9 [489 mg, quantitative yield] as an off-white solid.

Getting connection 11.

A 500 ml three-necked flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet was charged with 10 (9.00 g, 29.8 mmol, 1.00 equiv.) and acetonitrile (180 ml, 20 volumes). A solution of Oxone™ (45.9 g, 0.15 mol, 5.00 equiv.) in water (180 mL, 20 vols) was added to the batch over 20 minutes. The reaction mixture was stirred for 2 hours and ion pair chromatography confirmed that the reaction was complete. The reaction mixture was concentrated to 1/2 the original volume and was extracted with dichloromethane DCM (4x10 volumes). The organic layers were combined; filtered through a fine pore filter and concentrated to ~10 volumes. The product crystallized slowly upon addition of heptanes (~30 vols). The mixture was cooled to 0°C and the product was filtered and dried in vacuo at 40°C for 16 h to give 11 [9.45 g, 95% yield] as an off-white solid with >99% AUC purity. ¹ H-NMR (CDCl ₃ ): δ 9.24 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 3.89 (d, J=2.0 Hz, 2H), 3.43 (s, 3H), 2.98 (m, 2H), 2.10 (m, 2H), 1.86 (m, 3H), 1.50 (m, 3H). LCMS (ESI, m/z=335.2 [M+H]).

Getting connection 13.

A 250 ml single-necked flask equipped with an overhead mechanical stirrer, thermocouple, N2 inlet, and reflux condenser was charged with 4-chloro-2(methylthio)pyrimidine-5-carbaldehyde (2.00 g, 10.6 mmol, 1. 00 equiv.), spirolactam 4 (1.96 g, 11.7 mmol, 1.10 equiv.), DIPEA (2.74 g, 21.2 mmol, 2.00 equiv.) and tert-butanol (20 ml , 10 volumes). The reaction mixture was heated to 80 to 85° C. and after 24 h ion pair chromatography confirmed that no aldehyde 12 remained. The reaction mixture was cooled to room temperature and concentrated to a residue which was loaded onto a silica gel column. The product was eluted with ethyl acetate/heptanes (0 to 100%). Fractions containing product were recovered and concentrated to give 13 [0.98 g, 29% yield] as an off-white solid.

Obtaining compound 14.

A 500 mL three-necked flask equipped with an overhead mechanical stirrer, thermocouple, and N2 inlet was charged with 13 [0.98 g, 3.00 mmol, 1.00 equiv.], Boc anhydride (4.90 g, 21 .5 mmol, 7.00 equiv.), DMAP (36 mg, 0.30 mmol, 0.10 equiv.) and dichloromethane (7 ml, 7 volumes). The reaction mixture was stirred for 3 h at RT. Ion pair chromatography confirmed that no starting materials remained. The reaction mixture was cooled to room temperature and concentrated to a residue which was loaded onto a silica gel column. The product was eluted with ethyl acetate/heptanes (0 to 100%). Fractions containing product were recovered and concentrated to give 14 [0.98 g, 29% yield] as an off-white solid.

Get Compound 15.

To a suspension of methyl glycinate (500 g, 3.98 mol, 1 equiv) in DCM (10 L) was added TEA at RT under nitrogen, followed by cyclohexanone (781 g, 7.96 mol, 2 equiv) dropwise within 15 min. TMSCN (591 g, 5.97 mol, 1.5 equiv.) was added dropwise to the resulting mixture over 1 h while maintaining the temperature inside the reaction mixture below 35°C. After stirring at RT for 2 h, the suspension became clear. The progress of the reaction was monitored by H-NMR.

When the methyl glycinate was completely consumed, as shown by H-NMR analysis, the reaction mixture was quenched with water (5 L). The layers were separated. The aqueous layer was extracted with DCM (1 L). The combined organic phase was washed with water (5 lx2) and dried over Na ₂ SO ₄ (1.5 kg). After filtration and concentration, 1.24 kg of crude product 15 was obtained as an oil.

The crude product 15 was dissolved in IPA (4 L). The solution was treated with a solution of HCl/IPA (4.4 mol/l, 1.1 l) at RT. A large amount of solid precipitated during the addition. The resulting suspension was stirred for 2 hours. The solid was collected under vacuum.

- 48 042733 by filtration and washed with MTBE (800 ml). 819 g of pure 15 was obtained as a white solid. The yield was 88.4%. ¹ H-NMR (300 MHz, CD3OD) 4.20 (s, 2H), 3.88 (s, 3H), 2.30-2.40 (d, J=12 Hz,

2H), 1.95-2.02 (d, J=12 Hz), 2H), 1.55-1.85 (m, 5H), 1.20-1.40 (m, 1H).

Preparation of compound 16.

To a solution of 15 (10 g, 43 mmol) in MeOH (100 ml) was added a methanolic solution of hydrogen chloride (2.44 mol/l, 35.3 ml, 2 equiv.) and PtO ₂ (0.5 g, 5 wt. %). The reaction suspension was stirred with hydrogen bubbling at 40° C. for 6 h. H-NMR analysis showed consumption of compound 15. K ₂ CO ₃ (15 g, 108 mmol, 2.5 equiv.) was added to the reaction mixture, and the mixture was stirred in for 3 hours. The suspension was filtered and the filtrate was concentrated to dryness. The residual oil was diluted with DCM (100 ml) and the resulting suspension stirred for 3 hours. After filtration, the filtrate was concentrated to give crude 16 (6.6 g) as an oil. Crude 16 was diluted with EtOAc/hexane (1:1, 18 mL) at RT for 2 h. After filtration, 16 (4 g) was isolated. The resulting 16 was dissolved in DCM (16.7 ml) and hexane (100 ml) was added dropwise to precipitate the product. After additional stirring for 1 hour, 2.8 g of pure 16 was isolated as a white solid. The yield was 39%. HPLC purity was 98.3%; MS (ESI): 169.2 (MH ⁺ ); ¹ H-NMR (300 MHz, D2O), 3.23 (s, 3H), 3.07 (s, 3H), 1.37-1.49 (m, 10H).

Receiving compound 19.

5-(4-Methylpiperazin-1-yl)pyridine-2-amine (803.1 g; 3.0 equivalents based on sulfone 11) was charged into a 22 L flask. The flask was purged with N2 and anhydrous THF (12.4 kg) was added. The resulting black-violet solution was cooled in an ice bath to <5°C. 1M LiHMDS (4.7 L; 1.2 equivalents based on sulfone 11) was added via addition funnel in three equal additions to maintain the temperature below 10°C. Upon completion of the addition, the reaction mixture was heated to 16°C. Sulfone 11 (455.1 g, 1.00 eq) was added in five portions. The reaction was continued until HPLC analysis of the IPC sample indicated that less than 3% of sulfone 11 remained. To quench the reaction, the contents of the 22 L flask were transferred to a 100 L flask containing water. After stirring for 30 min at <30°C, the crude product was collected by filtration, washed with water and dried to give 19 (387 g, 99.1% purity, 63.7% yield).

Getting connection 20.

5-(4-Isopropylpiperazin-1-yl)pyridine-2-amine (1976.2 g; 3.0 equivalents based on sulfone 11) was charged into a 50 L flask. The flask was purged with N ₂ and anhydrous THF (10.7 kg) was added. The resulting black-violet solution was cooled in an ice bath to <5°C. 1M LiHMDS (9.6 kg; 3.6 equivalents in terms of sulfone) was added through an addition funnel at such a rate as to maintain the temperature below 10°C. After completion of the addition, the reaction mixture was heated to 16° C. for 120 min, removing the ice bath. Sulfone (1000 g; 1.00 mol) was added in five portions. The reaction was continued until analysis of the IPC sample by HPLC showed that less than 1% of sulfone 11 remained. After completion of the reaction, ammonium chloride was added to the reaction mixture. The mixture was stirred at <32° C. for at least 30 minutes and the solids were collected by filtration to give 20 (900 g, 99.1% purity, 64.2% yield).

Alternative route to spirolactam via cyclohexanone.

Scheme 2-7.

In one embodiment, spirolactam is prepared according to the synthesis scheme above. By reducing the nitrile group before adding the glycinate group, the reaction sequence proceeds in higher yield. The chemical reactions used in step 1 are described in the literature (J. Org. Chem. 2005, 70, 8027-8034) and were performed on a kilogram scale. The chemical reactions to convert compound 24 to spirolactam have also been demonstrated on the kilogram scale. Boc-protection of compound 23 is carried out at -70°C to limit the formation of di-Boc-protected product. Experimental details of trial reactions with 200 g are described below.

- 49 042733

200 g of cyclohexanone 21 was converted to 22 using Ti(Oi-Pr) ₄ /TMSCN/NH ₃ . Work-up gave 213 g of compound 22. H-NMR was pure. The yield was 84%. Titanium salts were removed by vacuum filtration. In one embodiment, salt.

Stage 2

Stage 1

_6NH2

190 g of compound 22 was mixed with LAH (2 eq) in MTBE for 30 min at 45°C. After treatment, 148 g of crude 23.

Stage 3

Vos I

24

136 g of crude 23 from step 2 was converted to 24 with 0.9 eq Boc ₂ O at -70°C. The reaction was completed and processed. After concentration, 188 g of compound 24 was obtained. The yield was 86%. The H-NMR and C-NMR spectra confirmed that the compound was pure.

Stage 4

stage 4 25

188 g of compound 24 was treated with methyl 2-bromoacetate and K2CO3 in acetonitrile to give compound 25. 247 g of crude 25 was obtained.

Stage 5

26

247 g of compound 25 was subjected to TFA in DCE at reflux to give compound 26. After workup, 112 g of compound 26 was obtained as a TFA salt. H-NMR was clean.

Stage 6

27

Compound 26 was stirred in EtOH in the presence at RT overnight to give compound 27. In one embodiment, DCM is used as solvent instead of EtOH.

Example 3 Removal of Residual Palladium from Step 5, Scheme 2-1.

Since palladium was used in step 5 of scheme 2-1, the levels of residual Pd were determined by

Claims (41)

present at subsequent stages of synthesis. Tab. 2 below and FIG. 3 show the levels of palladium in the recovered solids. table 2 Stage Stage 5 Stage 6 Stage 7 19 Facebook 19 Salt Pd ppm 14700 +779 164 19 14 Was isolated material after stage 5, containing 1.47% (14700 ppm) residual palladium. The data obtained represents the highest level of palladium in the worst case. The operating conditions in the latter stages ensured that almost all of the palladium was purified and the final product, the 19 bis HCl salt, contained 14 ppm. Pd, which is below the standard level of 20 ppm. Pd levels are likely to be even lower after optimization of catalyst loading in stage 5. The method developed in this route was a significant improvement over the method used for the first generation synthesis. Overall, the scheme consists of seven steps with five isolations, all by crystallization. The synthesis does not use silica gel column chromatography, making the process very scalable. The operating conditions of the process can ensure successful purification of 1.47% residual palladium after step 5 of scheme 2-1. The present invention has been described with reference to embodiments of the invention. However, those skilled in the art will appreciate that various modifications and changes may be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the present description is to be considered in an illustrative and not a limiting sense, and all such modifications are intended to be included within the scope of the invention. CLAIM 1. Method for preparing a compound of the formula Η 'Sh Η Ν ^Χ Η involving the reaction of pyrrolo[2,3-d]pyrimidine of the formula ox ^xlox XX χθχ° Ό. aXW ^Η /Ά· - ⁷ 0Χ° ϊΧΎΧ 4 ΝΗ ' _νη /—ν' ^η '—Ζ, _or \—/, 2'-(C ₁ -C ₃ -alkylsulfonyl or C ₁ -C ₃ -alkylsulfinyl) lactam- - 51 042733 about in which R ¹ is selected from: methyl, phenyl, C ₁ -C ₃ haloalkyl and benzyl; and represents the presence or absence of a double bond; with a suitable base and a heteroarylamine selected from: in a polar aprotic solvent; in which the ratio of heteroarylamine and 2'-(C ₁ -C ₃ alkylsulfonyl or C ₁ -C ₃ -alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine is at least 2:1, and the reaction yield is more than 50 % to obtain the specified compound. 2. The method according to claim 1, in which 2'-(C ₁ -C ₃ -alkylsulfonyl or C ₁ -C ₃ -alkylsulfinyl) lactampyrrolo[2,3-d]pyrimidine is added over a period of time of at least 30 min. 3. The method according to claim 1, in which 2'-(C ₁ -C ₃ -alkylsulfonyl or C ₁ -C ₃ -alkylsulfinyl)lactampyrrolo[2,3-d]pyrimidine is added in portions. 4. The method according to claim 1, further comprising obtaining 2'-(C ₁ -C ₃ -alkylsulfonyl or C 1-C 3 alkylsulfinyl)lactam-pyrrolo[2,3-d]pyrimidine by selective oxidation of 2'-(C ₁ -C ₃ alkylthio)lactam-pyrrolo[2,3-d]pyrimidine as an oxidizing agent in a solvent or mixture of solvents. 5. The method of claim 4 wherein the oxidizing agent is selected from: potassium peroxomonosulfate, hydrogen peroxide, meta-chloroperoxybenzoic acid (mCPBA), sodium hypochlorite and sodium chlorite. 6. The method of claim 5 wherein the oxidizing agent is potassium peroxomonosulfate. 7. Process according to claim 4, wherein the solvent or solvent mixture is selected from: N,N-dimethylacetamide (DMAc), dichloromethane (DCM), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), trifluoroacetic acid (TFA), acetonitrile (ACN), 4-dimethylaminopyridine (DMAP), water, acetic acid, acetone, dioxane, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexanes, diethyl ether, diglyme, dimethoxyethane (DME), dimethyl sulfoxide (DMSO), ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, hexamethylphosphoramide (HMPA), methanol, methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidone (NMP), pentane, pyridine, toluene , hydrochloric acid and triethylamine. 8. The method of claim 7 wherein the solvent or solvent mixture is selected from: ACN, water and dioxane. 9. The method of claim 8 wherein the solvent mixture is water and ACN. 10. The method according to claim 4, further comprising obtaining 2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3b]pyrimidine by removing the leaving group from the 5'-leaving group-2'-(C ₁ - C ₃ -alkylthio)lactampyrrolo[2,3-d]pyrimidine with a suitable leaving group cleaving reagent and a suitable organometallic catalyst. 11. The method according to claim 10, in which 2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-d]pyrimidine is a compound of formula IV and 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-d]pyrimidine is a compound of formula III - 52 042733 where -----2 and R ¹ are defined above; is a 6-carbon carbocycle spiro-linked to a lactam ring; R ² is hydrogen; And R ⁴ is selected from: hydrogen, -S(O) ₂ -C ₁ -C ₃ -alkyl, -S(O) ₂ -C ₁ -C ₃ haloalkyl, -S(O) ₂ -(C ₆ -or C ₁₀ -)aryl and -S(O) ₂ -benzyl. 12. The method of claim 10 wherein the suitable organometallic catalyst is a palladium catalyst. 13. The method of claim 10 wherein the leaving group is tosylate (-OTs). 14. The method of claim 10 wherein the leaving group is a triflate (-OTf). 15. The method of claim 10 wherein the suitable leaving group cleaving reagent is tri-C1-C3 alkylsilane. 16. The method of claim 15 wherein the tri-C ₁ -C ₃ alkylsilane is triethylsilane. 17. The method according to claim 10, further comprising obtaining a 5'-leaving group-2'-(C ₁ -C ₃ alkylthio)lactam-pyrrolo[2,3-b]pyrimidine from 5'-hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3d]pyrimidine with a suitable leaving group introducing reagent. 18. The method according to claim 17, in which the 5'-leaving group-2'-(C ₁ -C3-alkylthio) lactam-pyrrolo[2,3d]pyrimidine and 5'-hydroxyl-2'-(C ₁ -C _3- alkylthio)-lactam-pyrrolo[2,3-c1]pyrimidine is a compound of formula III. 19. The method of claim 17 wherein the leaving group is tosylate (-OTs). 20. The method of claim 17 wherein the leaving group is a triflate (-OTf). 21. The method of claim 19, wherein a suitable leaving group introducing reagent is triflic anhydride, Tf-Cl, tosyl anhydride, or Ts-Cl. 22. The method according to claim 17, further comprising obtaining 5'-hydroxyl-2'-(C ₁ -C ₃ alkylthio)lactam-pyrrolo[2,3-b]pyrimidine from C ₁ -C ₃ -alkyl-2-( C ₁ -C ₃ -alkylthio)-4-(lactam)pyrimidine-5carboxylate by intramolecular cyclization with a suitable base. 23. The method according to claim 22, in which 5'-hydroxyl-2'-(C ₁ -C3-alkylthio) lactam-pyrrolo[2,3-b]pyrimidine is a compound of formula III and C ₁ -C ₃ -alkyl -2-(C ₁ -C ₃ -alkylthio)-4-(lactam)pyrimidine-5carboxylate is a compound of formula II C> ^-R ⁵ O |Λ>-Ν NR ² R ¹ -s (c) Ο (Π) where CZ-^, R ¹ and R ² are defined above; And R ⁵ is C _g C ₃ -alkoxy. 24. The method according to claim 22, further comprising obtaining C ₁ -C ₃ -alkyl-2- (C ₁ -C ₃ -alkylthio) -4 (lactam) pyrimidine-5-carboxylate from C ₁ -C ₃ -alkyl-4 -halogen-2-(C ₁ -C ₃ -alkylthio)pyrimidine-5-carboxylate by nucleophilic attack with an aminolactam in a suitable organic solvent with a suitable base. 25. The method according to claim 24, in which C ₁ -C ₃ -alkyl-2- (C ₁ -C ₃ -alkylthio) -4- (lactam) pyrimidine-5-carboxylate is a compound of formula II and aminolactam is a compound formula I ( C ) where ' is defined above, and R ² and R ³ are hydrogen. 26. The method according to claim 1, in which 2'-(C ₁ -C ₃ -alkylsulfonyl or C ₁ -C ₃ -alkylsulfinyl)lactam- - 53 042733 pyrrolo[2,3-d]pyrimidine is a 2'-(C ₁ -C ₃ -alkylsulfonyl)lactam-pyrrolo[2,3d]pyrimidine. 27. The method of claim 1, wherein said compound is 28. The method of claim 1, wherein said compound is 29. The method according to claim 1 or 2, wherein the temperature is maintained at 18°C or lower. 30. The method according to claim 1 or 2, wherein the temperature is maintained at 16°C or lower. 31. The method according to claim 1 or 2, wherein the temperature is maintained at 14°C or lower. 32. The method of claim 1 or 2, wherein the temperature is maintained at 12°C or lower. 33. The method according to claim 1 or 2, wherein the temperature is maintained at 10°C or lower. 34. The method according to claim 1 or 2, in which the temperature is maintained from 0 to 50°C. 35. The method according to claim 1 or 2, in which the temperature is maintained from 15 to 30°C. 36. A method for obtaining 2'-(C ₁ -C ₃ -αkylthio)lactαm-pyrrolo[2,3-d]pyrimidine, including: a) reaction of the 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-d]pyrimidine with a suitable leaving group cleaving reagent and a suitable organometallic catalyst to remove the leaving group and obtain 2' -(C1- _C3 -alkylthio)lactam-pyrrolo[2,3d]n-pyrimidine; b) obtaining 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-b]pyrimidine from 5'hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam -pyrrolo[2,3-4]pyrimidine with a suitable leaving group introducing reagent; c) obtaining 5'-hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-d]pyrimidine from C1-C ₃ -alkyl-2(C ₁ -C ₃ -alkylthio)- 4-(lactam)pyrimidine-5-carboxylate by intramolecular cyclization with a suitable base; and d) obtaining C ₁ -C ₃ -alkyl-2- (C ₁ -C ₃ -alkylthio) -4- (lactam) pyrimidine-5-carboxylate from C 1 -C ₃ -alkyl4-halogen-2- (C ₁ -C ₃ -alkylthio)pyrimidine-5-carboxylate by nucleophilic attack with an aminolactam in a suitable organic solvent with a suitable base; moreover, 2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-4]pyrimidine is a compound of formula IV, 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio)lactam- pyrrolo[2,3-d]pyrimidine and 5'-hydroxyl-2'-(C ₁ C ₃ -alkylthio) lactαm-pyrrolo[2,3-d]pyrimidine are compounds of formula III, C1-C3 alkyl-2-( C1-C3 _- alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of formula II and aminolactam is a compound of formula I: represents the presence or absence of a double bond; Where is a 6-carbon carbocycle spiro-linked to a lactam ring; R ¹ is selected from: methyl, phenyl, C1- _C3 haloalkyl and benzyl; R ² and R ³ are independently selected from hydrogen; - 54 042733 R ⁴ is selected from: hydrogen, -S(O) ₂ -C ₁ -C ₃ -alkyl, -S(O) ₂ -C ₁ -C ₃ -haloalkyl, -8(O) ₂ -(C ₆ -or C ₁₀ -) aryl and -S(O) ₂ -benzyl; And R ⁵ is C1- _C3 alkoxy. 37. A method for obtaining a 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio) lactam-pyrrolo[2,3-d]pyrimidine, including: a) reacting 5'-hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam-pyrrolo[2,3-d]pyrimidine with a suitable leaving group introducing reagent to obtain a 5'-leaving group-2'-(C1 -C ₃ alkylthio)lactam-pyrrolo[2,3-d]pyrimidine; b) obtaining 5'-hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam-nirrolo[2,3-d]pyrimidine from C1-C ₃ -alkyl-2(C1-C ₃ -alkylthio)-4 -(lactam)pyrimidine-5-carboxylate by intramolecular cyclization with a suitable base; And c) obtaining C ₁ -C ₃ -alkyl-2- (C ₁ -C ₃ -alkylthio) -4- (lactam) pyrimidine-5-carboxylate from C 1 -C ₃ -alkyl 4-halogen-2- (C 1 -C ₃ -alkylthio)pyrimidine-5-carboxylate by nucleophilic attack with an aminolactam in a suitable organic solvent with a suitable base; moreover, the 5'-leaving group-2'-(C ₁ -C ₃ -alkylthio)lactam-npyrrolo[2,3-d]pyrimidine and 5'-hydroxyl-2'(C ₁ -C ₃ -alkylthio)lactam-pyrrolo [2,3-d]pyrimidine are compounds of formula III, C1-C3 alkyl-2-(C1-C ₃ -alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of formula II, and aminolactam is a compound formula I: where ------ represents the presence or absence of a double bond; w.... h__' is a carbocycle of 6 carbon atoms spiro-linked to the lactam ring; R ¹ is selected from: methyl, phenyl, C1-C3 haloalkyl and benzyl; R ² and R ³ are independently selected from hydrogen; R ⁴ is selected from: hydrogen, -S(O) ₂ -C ₁ -C ₃ -alkyl, -S(O) ₂ -C ₁ -C ₃ -haloalkyl, -8(O) ₂ -(C ₆ -or C ₁₀ -) aryl and -S(O) ₂ -benzyl; And R ⁵ is C ₁ -C ₃ alkoxy. 38. A method for producing 5'-hydroxyl-2'-(C1-C ₃ -alkylthio)lactam-pyrrolo[2,3-b]pyrimidine, including: a) intramolecular cyclization of C1-C ₃ -alkyl-2-(C1-C ₃ -alkylthio)-4-(lactam)pyrimidine-5-carboxylate with a suitable base to obtain 5'-hydroxyl-2'-(C ₁ -C ₃ - alkylthio)lactampyrrolo[2,3-d]pyrimidine; and b) obtaining C1-C ₃ -alkyl-2-(C1-C ₃ -alkylthio)-4-(lactam)pyrimidine-5-carboxylate from C1-C ₃ -alkyl4-halogen-2-(C1-C ₃ -alkylthio )pyrimidine-5-carboxylate by nucleophilic attack with an aminolactam in a suitable organic solvent with a suitable base; moreover, 5'-hydroxyl-2'-(C ₁ -C ₃ -alkylthio)lactam-npyrrolo[2,3-d]pyrimidine is a compound of formula III, C1-C ₃ -alkyl-2-(C1-C ₃ - alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of formula II and aminolactam is a compound of formula I: where ------ represents the presence or absence of a double bond; ω _ _£ . is a 6-carbon carbocycle spiro-linked to a lactam ring; R ¹ is selected from: methyl, phenyl, C ₁ -C ₃ haloalkyl and benzyl; R ² and R ³ are independently selected from hydrogen; R ⁴ is selected from: hydrogen, -S(O) ₂ -C ₁ -C ₃ -alkyl, -S(O) ₂ -C ₁ -C ₃ -haloalkyl, -8(O) ₂ -(C ₆ -or C ₁₀ -) aryl and -S(O) ₂ -benzyl; And R ⁵ is C1- _C3 alkoxy. 39. A method for producing C1-C ₃ -alkyl-2-(C1-C ₃ -alkylthio) -4-(lactam) pyrimidine-5-carboxylate, including: - 55 042733 a) nucleophilic attack in a suitable organic solvent with a suitable base C ₁ -C ₃ -alkyl-4-halogen-2-(C1-C ₃ -alkylthio)pyrimidine-5-carboxylate with a compound of formula I to obtain C ₁ -C ₃ -alkyl-2-(C ₁ -C ₃ -alkylthio )-4-(lactam)pyrimidine-5-carboxylate; b) obtaining a compound of formula I from a compound of formula VIII by intramolecular cyclization; and c) obtaining a compound of formula VIII by reductive amination of a compound of formula VII with methyl 2-oxoacetate; where is a carbocycle of 6 carbon atoms, connected by spiro type with a lactam ring; R ² and R ³ are independently selected from hydrogen. 40. A method for producing C1-C ₃ -alkyl-2-(C1-C ₃ -alkylthio) -4-(lactam) pyrimidine-5-carboxylate, including: a) nucleophilic attack in a suitable organic solvent with a suitable base C1-C ₃ -alkyl-4-halo-2-(C1-C ₃ -alkylthio)pyrimidine-5-carboxylate with a compound of formula I to obtain C1-C ₃ -alkyl-2 -(C1- _C3 alkylthio)-4-(lactam)pyrimidine-5-carboxylate; b) obtaining a compound of formula I from a compound of formula IX by reducing the cyano group to an amine followed by intramolecular cyclization; c) obtaining a compound of formula IX by condensation of a C1- _C3 alkylglycinate with cyclohexanone in the presence of TMSCN and a base; where is a carbocycle of 6 carbon atoms, connected by spiro type with a lactam ring; R ² and R ³ are independently selected from hydrogen; alkyl in a compound of formula IX is C1- _C3 alkyl. 41. A method for obtaining a compound of formula I, including a) intramolecular cyclization of a compound of formula VIII to obtain a compound of formula I; b) Preparation of a compound of formula VIII by reductive amination of a compound of formula VII with methyl 2-oxoacetate -