# US 10,865,210 B2 · Synthesis of n-(heteroaryl)-pyrrolo[3,2-d]pyrimidin-2-amines

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- Number: US 10,865,210 B2
- Document ID: US10865210B2
- Status: Granted
- Kind: B2
- Application number: 16/230,381
- Filed: 2018-12-21
- Published: 2019-05-09
- Granted: 2020-12-15
- Earliest claimed: 2016-07-01
- Assignees: G1 Therapeutics, Inc.
- Applicants: G1 Therapeutics, Inc.
- Inventors: Alexander Smith; Hannah S. White; Francis Xavier Tavares; Sergiy Krasutsky; Jian-Xie Chen; Roberta L. Dorrow; Hua Zhong
- Web page: https://patentgrep.com/patent/US10865210B2

## CPC

- C07D 487/20: Spiro-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention is in the area of synthesizing pyrimidine-based compounds useful in the treatment of disorders involving abnormal cellular proliferation, including but not limited to tumors and cancers.

## Claims

### Claim 1

A process to prepare a 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine comprising: reacting a 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine with a heteroaryl amine, wherein the ratio of heteroaryl amine to 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is at least about 2 to 1 and the yield of the reaction is over about 50%, to afford the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine,
wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is a compound of Formula:
wherein:
Z is —(CH2)x—, wherein x is 1, 2, 3 or 4; or —O—(CH2)z— wherein z is 2, 3 or 4;
R2 is independently selected from the group consisting of hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl;
each R6 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 a carbon in the chain and two R6's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
y is 0, 1, 2, 3 or 4;
R12 is
R7 is -(alkylene)m-heterocyclo, -(alkylene)m-heteroaryl, -(alkylene)m-NR8R9, -(alkylene)m-C(O)—NR8R9; -(alkylene)m-C(O)—O-alkyl; -(alkylene)m-O—R10, -(alkylene)m-S(O)n—R10, or -(alkylene)m-S(O)n—NR8R9; any of which ma be optionally independently substituted with one or more R′ groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring;
R8 and R9 at each occurrence are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl, any of which may be optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring; or
R8 and R9 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more Rx groups as allowed by valance, and wherein two Rx groups bound to the same or adjacent atom may optionally combine to form a ring;
R10 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may be optionally independently substituted with one or more Rx groups as allowed by valance;
Rx at each occurrence is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl;
n is 0, 1, or 2; and
m is 0 or 1.

### Claim 2 (depends on 1)

The process of claim 1, wherein the process is conducted with a temperature that is maintained from about 0 to about 50° C.

### Claim 3 (depends on 1)

The process of claim 1, wherein the process is conducted with a temperature that is maintained from about 15 to about 30° C.

### Claim 4 (depends on 1)

The process of claim 1, wherein the process is conducted with a temperature that is maintained at or below 18° C.

### Claim 5 (depends on 1)

The process of claim 1, wherein the process is conducted with a temperature that is maintained at or below 10° C.

### Claim 6 (depends on 1)

The process of claim 1, wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is added over a time period of at least about 30 minutes.

### Claim 7 (depends on 6)

The process of claim 6, wherein the temperature is maintained from about 0 to about 50° C.

### Claim 8 (depends on 1)

The process of claim 1, wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is added portion wise.

### Claim 9 (depends on 1)

The process of claim 1 further comprising: preparing the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine by selectively oxidizing a 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine with an oxidant in a solvent or mixture of solvents.

### Claim 10 (depends on 9)

The process of claim 9, wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine and 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine are compounds of Formula IV:
wherein:
represents the presence or absence of a double bond;
represents a carbocycle of 3 to 8 carbons connected in a spiro-fashion to the lactam ring wherein the spirocycle is optionally substituted;
R1 is selected from: alkyl, aryl, haloalkyl, and arylalkyl; and
R2 is selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl.

### Claim 11 (depends on 10)

The process of claim 10, wherein the oxidant is selected from: oxone, hydrogen peroxide, mCPBA, sodium hypochlorite, and sodium chlorite.

### Claim 12 (depends on 11)

The process of claim 11, wherein the oxidant is oxone.

### Claim 13 (depends on 10)

The process of claim 10, wherein the solvent or mixture of solvents is selected from: 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 triethyl amine.

### Claim 14 (depends on 13)

The process of claim 13, wherein the solvent or mixture of solvents is selected from ACN, water, and dioxane.

### Claim 15 (depends on 14)

The process of claim 14, wherein the mixture of solvents is water and ACN.

### Claim 16 (depends on 10)

The process of claim 10 further comprising: preparing the 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine by removing the leaving group from a 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine with a suitable reagent.

### Claim 17 (depends on 16)

The process of claim 16, wherein the 2′-(alkylthio)-lactam-pyrrolo[3,2-d]pyrimidine is a compound of Formula IV and the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula III:
wherein:
R4 is selected from: hydrogen, silyl, haloalkyl, —C(O)alkyl, —S(O)2alkyl, —S(O)2haloalkyl, —S(O)2aryl, and —S(O)2arylalkyl.

### Claim 18 (depends on 17)

The process of claim 17 further comprising a palladium catalyst.

### Claim 19 (depends on 17)

The process of claim 17, wherein the leaving group is tosylate (-OTs).

### Claim 20 (depends on 17)

The process of claim 17, wherein the leaving group is triflate (-OTf).

### Claim 21 (depends on 17)

The process of claim 17, wherein the suitable reagent is a trialkylsilane.

### Claim 22 (depends on 21)

The process of claim 21, wherein the trialkylsilane is triethylsilane.

### Claim 23 (depends on 17)

The process of claim 17 further comprising: preparing the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine from a 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine with a suitable reagent.

### Claim 24 (depends on 23)

The process of claim 23 wherein the 5′-leaving group-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine and 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine are compounds of Formula III.

### Claim 25 (depends on 23)

The process of claim 23, wherein the leaving group is tosylate (-OTs).

### Claim 26 (depends on 23)

The process of claim 23, wherein the leaving group is triflate (-OTf).

### Claim 27 (depends on 23)

The process of claim 23, wherein the suitable reagent is triflic anhydride, Tf-Cl, tosyl anhydride, or Ts-Cl.

### Claim 28 (depends on 23)

The process of claim 23 further comprising: preparing the 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine from an alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate by an intramolecular cyclization.

### Claim 29 (depends on 28)

The process of claim 28, wherein the 5′-hydroxyl-2′-(alkylthio)-lactam-pyrrolo[2,3-d]pyrimidine is a compound of Formula III and the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate is a compound of Formula II:
wherein:
R5 is selected from: hydrogen, halogen, —N(alkyl)(alkoxy), —NCH3OMe, alkoxy, aryloxy, —OCH2aryl, —OC(O)alkyl, —OC(O)aryl, and —OC(O)arylalkyl.

### Claim 30 (depends on 29)

The process of claim 29 further comprising: preparing the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5-carboxylate from an alkyl 4-halo-2-(alkylthio)pyrimidine-5-carboxylate by nucleophilic attack of a lactam amine.

### Claim 31 (depends on 30)

The process of claim 30, wherein the alkyl 2-(alkylthio)-4-(lactam)pyrimidine-5 carboxylate is a compound of Formula II and the lactam amine is a compound of Formula I:
wherein:
R2 and R3 is selected from hydrogen, carbamate, aryl, alkyl, allyl, and arylalkyl.

### Claim 32 (depends on 1)

The process of claim 1 wherein the 2′-(alkylsulfonyl or alkylsulfinyl)-lactam-pyrrolo[3,2-d]pyrimidine is a 2′-(alkylsulfonyl)-lactam-pyrrolo[3,2-d]pyrimidine.

### Claim 33 (depends on 1)

The process of claim 1 wherein Z is —(CH2)2—.

### Claim 34 (depends on 33)

The process of claim 33 wherein R2 is hydrogen.

### Claim 35 (depends on 34)

The process of claim 34 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine of is selected from:

### Claim 36 (depends on 35)

The process of claim 35 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is:

### Claim 37 (depends on 35)

The process of claim 35 wherein the 2′-(heteroaryl)-lactam-pyrrolo[3,2-d]pyrimidine is: