# US 11,306,100 B2 · Spirooxindole compounds as GSK3B inhibitors and process for preparation thereof

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- Number: US 11,306,100 B2
- Document ID: US11306100B2
- Status: Granted
- Kind: B2
- Application number: 16/492,359
- Filed: 2018-03-09
- Published: 2021-09-16
- Granted: 2022-04-19
- Earliest claimed: 2017-03-10
- Applicants: Council of Scientific & Industrial Research
- Inventors: Prathama S. Mainkar; Mohammad Abdul Sattar; Pitchakuntla Mallesham; Togapur Pavan Kumar; Divya Duscharla; Ummanni Ramesh; Srivari Chandrasekhar
- Web page: https://patentgrep.com/patent/US11306100B2

## CPC

- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of general formulae I useful as GSK3β inhibitors and their anticancer potential and process for preparation of these spirooxindoles. wherein Z is hydrogen, halogen, hydroxy, alkoxy, cyano, nitro; Ring A is a five membered or six membered or seven membered optionally containing additional hetero atom in the ring X is optionally CH2 Ring B is triazole or cyclic amine alone or with one or more hetero atoms part of the ring and optionally substituted with one or more substituents Y is hydrogen, alkoxy, aryloxy, hydroxy, ester, amide, amino, alkyl or aryl, heteroaryl, wherein these substituents are optionally substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde, wherein these substituents are further substituted with one or more halogen, hydroxy, alkoxy, alkyl, aryl, heteroaryl, aryloxy, nitro, cyano, ester, aldehyde.

## Claims

### Claim 1

A Spirooxindole compound of formula I
wherein
Z is hydrogen, halogen, hydroxy, alkoxy, cyano, or nitro;
Ring A is a five, six or seven membered ring optionally containing an additional hetero atom;
X is either absent or CH2;
Ring B is a triazole or a cyclic amine optionally internally substituted with one or more hetero atoms and optionally substituted with a single substituent Y;
Y is hydrogen, halogen, azide, hydroxymethyl, aryloxy, hydroxy, alkoxycarbonyl, amide, amino, alkyl, phenyl, pyridinyl, benzyl, or benzoyl, aminoalkyl, Y is optionally substituted with one or more of substituents Ya, wherein Ya is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl or aldehyde;
each Ya is optionally substituted with one or more substituents Yb, wherein Yb is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde; and
each Yb is optionally substituted with one or more substituents Yc, wherein Yc is of alkoxycarbonyl, halogen or alkyl.

### Claim 2 (depends on 1)

The compound as claimed in claim 1, represented by the compound of formula II
wherein
R is hydrogen, hydroxymethyl, aryloxy, hydroxy, alkoxycarbonyl, amide, amino, alkyl, phenyl, pyridinyl, benzyl, or benzoyl;
R is optionally substituted with one or more substituents Ra, wherein Ra is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or an aldehyde;
each Ra is optionally substituted with one or more substituents Rb, wherein Rb is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde; and
each Rb is optionally substituted with one or more substituents Rc, wherein Rc is alkoxycarbonyl, halogen or an alkyl.

### Claim 3 (depends on 1)

The compound as claimed in claim 1, selected from the group consisting of:
(AB-O) Ethyl 2-methyl-6-(2((1-(2′-oxo-4,5-dihydro-2H -spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)nicotinate
(AB-M) Ethyl 6-(5-fluoro-2-((1-((2′-oxo-4,5-dihydro-2H -spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2-methylnicotinate
(AB-N) Methyl-6-(5-chloro-2-((1-((2′-oxo-4,5-dihydro-2H -spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2-methylnicotinate
(AB-P) 2-((1-((2′-Oxo-4,5-dihydro-2H-spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde
(AB-W) Ethyl-6-(3,5-dichloro-2-((1-((2′-oxo-4,5-dihydro-2H-spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2-methylnicotinate
(AB-F) Ethyl-1-((2′-oxo-4,5-dihydro-2H-spiro[furan-3,3′-indoline]-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylate
(AB-C) 5-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-G) 5-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-E) 5-((4-(2-Hydroxypropan-2-yl)-1H- 1,2,3-triazol-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
and
(AB-D) 5-((4-(4-Nitrophenyl)-1H-1,2,3-triazol-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one

### Claim 4 (depends on 1)

The compound as claimed in claim 1, represented by the formula III:
wherein
ring B is a cyclic amine optionally internally substituted with one or more hetero atoms and substituted with a single substituent R, wherein R is hydrogen, alkoxy, aryloxy, hydroxy, alkoxycarbonyl, amide, amino, alkyl, phenyl, pyridinyl, benzyl, or benzoyl;
R is optionally substituted with one or more substituents Ra, wherein Ra is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde;
each Ra is optionally substituted with one or more of substituents Rb, wherein Rb is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde; and
each Rb is optionally substituted with one or more substituents Rc, wherein Rc is alkoxycarbonyl, halogen or alkyl.

### Claim 5 (depends on 1)

The compound as claimed in claim 1, selected from the group consisting of:
(AB-X) 5-((4-Phenylpiperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-K) 5-(Morpholinomethyl)-4,5-dihydro-2H-spiro [furan-3,3′-indolin]-2′-one
(AB-S) 5-((4-(Pyridin-2-yl)piperazin-1-yl)methyl)-4,5-dihydro-2H -spiro[furan-3,3′-indolin]-2′-one
(AB-U) 5-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-T) 5-((4-(4-Methoxyphenyl)piperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-Q) 5-((4-Benzoylpiperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-L) 5-(Thiomorpholinomethyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
(AB-R) 5((4-Benzylpiperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one
or
(AB-V) 5-((4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)methyl)-4,5-dihydro-2H-spiro[furan-3,3′-indolin]-2′-one

### Claim 6 (depends on 1)

The compound as claimed in claim 1, represented by formula IV:
wherein
R is hydrogen, alkoxy, aryloxy, hydroxy, alkoxycarbonyl, amide, amino, alkyl, phenyl, pyridinyl, benzyl, or benzoyl;
R is optionally substituted with one or more of substituents Ra, wherein Ra is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde;
each Ra is substituted with one or more substituents Rb, wherein Rb is halogen, hydroxy, alkoxy, alkyl, phenyl, pyridinyl, benzyl, benzoyl, aryloxy, nitro, cyano, alkoxycarbonyl, or aldehyde; and
each Rb is optionally substituted with one or more substituents Rc, wherein Rc is alkoxycarbonyl, halogen or alkyl.

### Claim 7 (depends on 1)

The compound as claimed in claim 1, selected from the group consisting of:
(AC-A) Ethyl 6-(5-fluoro-2-((1-(2-oxo-2′, 4′, 5′, 6′-tetrahydrospiro[indoline-3,3′-pyran]-5′-yl)-1H-1,2,3-triazol-4-yl)methoxy)-phenyl)-2-methylnicotinate
(AC-B) Ethyl 2-methyl-6-(2-((1-(2-oxo-2′,4′,5′,6′-tetrahydrospiro[indoline-3,3′-pyran]-5′-yl)-1H-1,2,3-triazol-4-yl)methoxy)-phenyl)nicotinate
(AC-C) Ethyl 6-(5-chloro-2-((1-(2-oxo-2′,4′,5′,6′-tetrahydrospiro [indoline-3,3′-pyran]-5′-y1)-1H-1,2,3-triazol-4- yl)methoxy)-phenyl)-2-methyl nicotinate
(AC-D) Ethyl 6-(3,5-dichloro-2-((1-(2-oxo-2′,4′,5′,6′-tetrahydrospiro-[indoline-3,3′-pyran]-5′-yl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2-methyl nicotinate
(AC-E) 2-((1-(2-Oxo-2′, 4′, 5′, 6′-tetrahydrospiro[indoline -3,3′-pyran]-5′-yl)-1H-1,2,3-triazol-4-yl) methoxy)benzaldehyde
(AC-F) 5′-(4-(Pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)-2′,4′,5′,6′-tetrahydrospiro[indoline-3,3′-pyran]-2-one
(AC-G) 5′-(4-(Hydroxy(phenyl)methyl)-1H-1,2,3-triazol-1-yl)-2′,4′,5′,6′-tetrahydro spiro[indoline-3,3′-pyran]-2-one
(AC-H) 5′-(4-((2-Nitrophenoxy)methyl)-1H-1,2,3-triazol-1-yl)-2′,4′,5′,6′-tetrahydro Spiro -[indoline-3,3′-pyran]-2-one
(AC-I) 5′-(4-((4-Chloro-2-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)-2′,4′,5′,6′-tetra hydrospiro[indoline-3,3′-pyran]-2-one
(AC-J) 5′-(4-((3-Hydroxyphenylamino)methyl)-1H-1,2,3-triazol-1-yl)-2′,4′, ′,6′-tetrahydrospiro[indoline-3,3′-pyran]-2-one
(AC-K) 5′-(4-((3-Aminophenoxy)methyl)-1H-1,2,3-triazol-1-yl) -2′,4′,5′,6′-tetrahydro spiro[indoline-3,3′-pyran]-2-one
or
(AC-L) 5′-(4-((5-Bromo-3-nitropyridin-2-yloxy) methyl)-1H-1,2,3-triazol-1-yl)-2′,4′,5′,6′-tetrahydrospiro[indoline-3,3′-pyran]-2-one

### Claim 8 (depends on 1)

A process for the preparation of a compound of claim 1 comprising the steps of:
a) allylation of oxindole;
b) protection of free amine groups in said oxindole with a boc group;
c) formylation of the product of (b) using formaldehyde;
d) removal of said boc group to give a free amine;
e) cyclisation of the product of (d) with iodine to give a spiro-iodo compound;
f) azidating said spiro-iodo compound with sodium azide to give a spiro-azide compound or reacting said spiro-iodo compound with a cyclic amine to give a cyclic amine based spirooxindole;
g) reacting the product of (f) with an alkyne to give a triazole based spirooxindole under click chemistry conditions.

### Claim 9 (depends on 1)

A method for inhibiting GSK3β activity comprising administering an amount of the compound of claim 1 to a subject sufficient to inhibit GSKβ activity.

### Claim 10 (depends on 1)

A method for treating pancreatic cancer comprising administering to a subject with pancreatic cancer, an amount of the compound of claim 1 to inhibit GSK3β activity.