EA042925B1 - CONDENSED BICYCLIC COMPOUNDS FOR USE AS UBIQUITIN-SPECIFIC PEPTIDASE INHIBITORS 30 - Google Patents

Description

Field of technology to which the invention relates

The invention provides new compounds and dosage forms thereof useful for inhibiting ubiquitin-specific peptidase 30, also known as ubiquitin-specific protease 30 (USP30).

State of the art

The ubiquitination system is a highly regulated process that influences a wide range of cellular activities and physiological processes. Dysregulation of this system is commonly associated with a number of human diseases, including cancer, neurodegenerative disorders, muscular dystrophies, and cardiomyopathies, among others (Popovic, et al., Nature Medicine 2014, 20, 1242-1253). Ubiquitination is a reversible process facilitated by a group of proteins known as deubiquitinating enzymes (DUBs) that deconjugate ubiquitin (Ub) from the substrate. Deubiquitinating enzymes (DUBs) are encoded by approximately 100 human genes and are divided into six families, with the largest family being formed by ubiquitin-specific proteases (USPs), with more than 50 members.

Ubiquitin regulates mitochondrial dynamics and biogenesis, influencing the abundance and functioning of these organelles. Mitochondria perform many functions to maintain cellular health in mammals, including producing ATP. As mitochondria age, they become damaged and lose metabolic function, and they begin to secrete proapoptotic proteins. Mitochondria are capable of regulating their qualitative state through the mechanism of mitophagy, which is the selective removal of damaged mitochondria from the cell. Based on studies conducted to understand what influences mitochondrial mitophagy, it has been suggested that ubiquitination of mitochondrial proteins appears to contribute to mitochondrial dynamics in mammalian cells by marking these proteins for inactivation. USP30 is a deubiquitinating enzyme embedded in the outer membrane of mitochondria, where it is involved in maintaining mitochondrial morphology. It is believed that overexpression of USP30 may lead to decreased mitophagy.

An association has been found between many age-associated diseases, particularly neurodegenerative disorders, and mitochondrial dysfunction and disruption of the ubiquitination system (Ross, et al., Int J Mol Sci. 2015, 16(8), 19458-19476). Impaired mitophagy as a result of inactivating mutations in the PINK1 and Parkin proteins can lead to the accumulation of damaged mitochondria and neuronal toxicity, and is thought to cause Parkinson's disease. USP30 is a mitochondrial deubiquitinating enzyme (DUB) that antagonizes the ligase activity of the Parkin protein and is a negative regulator of mitophagy. It is expected that inhibition of USP30 may promote mitophagy and restore mitochondrial health.

Accordingly, there is a need to develop compounds that can inhibit USP30 for therapeutic purposes.

The essence of the invention

The present invention provides compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is selected from N and CR ^x ;

V, Y and Z are selected from (i), (ii) or (iii):

(i) V represents C(O); Y is selected from C(O) and CR ^j R ^k and Z is selected from C(O) and CR ^j R ^k ;

(ii) V is selected from the chemical bond, C(O) and CR ^f R ^g ; Y is C(O) and Z is selected from C(O) and CR ^j R ^k ; or (iii) V is selected from the chemical bond, C(O) and CR ^f R ^g ; Y is selected from C(O) and CR ^j R ^k and Z is C(O);

L represents -(CH ₂ ) _n -;

n is 0, 1 or 2, wherein each methylene unit in L is optionally replaced by one C ₁ -C ₆ alkyl, and where if n is 2 then one methylene unit in L is optionally replaced by oxygen;

in each case R ^a , R ^b , R ^c , R ^d , Re, R ^f , R ^g , R ^h , Ri, R ^j , R ^k and R ^x are independently selected from hydrogen, halogen and C ₁ -C ₆ -alkyl ;

ring A is selected from C ₃ -C ₁₀ -cycloalkyl, 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and 5-10 membered heteroaryl containing from 1 to 3 heteroatoms, selected from nitrogen, oxygen and sulfur,

- 1 042925 where the ring A is optionally substituted by one or more W;

each W is independently selected from halogen, -OR, -CN, optionally substituted _{C 6} -alkyl, optionally substituted C 3 -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen , oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where the optionally substituted W group may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN, -NO2, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, -(CH ₂ ) _m (C ₃ -C ₁₀ -cycloalkyl), - (CH ₂ ) _m (3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl);

each R is independently selected from hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl and phenyl; and each m is independently 0 or 1.

Additional objects and advantages of the invention will be set forth in part in the description that follows, and in part will become apparent from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and achieved by the elements and combinations specifically set forth in the appended claims.

It should be understood that both the above general description and the following detailed description are for purposes of illustration and explanation only, and do not limit the scope of the claims.

Detailed Description of the Invention

Compounds of formula (I).

The present invention provides, among other things, chemical structures of formula (I)

and pharmaceutically acceptable forms thereof, wherein V, X, Y, Z, L, R ^a , R ^b , R ^c , R ^d , R ^e , R ^h , ^Ri and ring A are all defined above for formula (I) and described in classes and subclasses for formula (I), both individually and in combinations.

In at least one embodiment of formula (I)

Y is selected from C(O) and CRjR ^k ;

n represents 0;

R ^a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl;

^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh ,} Ri, Rj, ^Rk and ^Rx are each hydrogen;

ring A is a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W;

each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl, wherein the optionally substituted W group may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _m (3-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (C ₆ aryla);

each R represents phenyl and each m represents 1.

In at least one embodiment of formula (I)

V is selected from C(O) and CR ^f R ^g ;

X represents N;

Y represents C(O);

n represents 0;

R ^a represents hydrogen;

^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh ,} Ri, Rj, ^Rk and ^Rx are each hydrogen;

ring A is a 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W;

each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl,

- 2 042925 wherein the optionally substituted group W may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN and -(CH ₂ ) _m (phenyl);

each R represents phenyl and each m represents 1.

In at least one embodiment of formula (I), L is -(CH ₂ ) _n -, and n=0. In at least one embodiment, L is -(CH ₂ ) _n -, and n=1. In at least one embodiment, L is -(CH ₂ ) _n -, and n=2. In at least one embodiment, L is -(CH ₂ ) _n -, n=2, and L is substituted with alkyl. In at least one embodiment, L is selected from -(CH ₂ ) ₀ -, -CH2-, -CH2CH2- and -CH2CH(CH3)-.

In at least one embodiment of formula (I), n is 0.

In at least one embodiment of formula (I), ring A is selected from _C3 - _C10 cycloalkyl, a 3-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and 5-10- membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein ring A is optionally substituted with one or more W. In at least one embodiment, ring A is an optionally substituted 5-6 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In at least one embodiment, ring A is an optionally substituted 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. In at least one embodiment, ring A is an optionally substituted thiazolyl or pyrazolyl.

In some embodiments, the present invention provides compounds of formula (II'-a)

or pharmaceutically acceptable salts thereof, wherein R ^a and ring A are both defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (II'-b)

or pharmaceutically acceptable salts thereof, wherein R ^a , R ^x and ring A are collectively defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (II'-c)

or pharmaceutically acceptable salts thereof, wherein R ^a and ring A are both defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (II'-d)

or pharmaceutically acceptable salts thereof, wherein R ^a and ring A are both defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (II'-e) o

¥ or pharmaceutically acceptable salts thereof, wherein R ^a and ring A are both defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

- 3 042925

In some embodiments, the present invention provides compounds of formula (II'-g)

or pharmaceutically acceptable salts thereof, wherein R ^a , R ^x and ring A are collectively defined for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (III)

or pharmaceutically acceptable salts thereof, wherein V, X, Y, Z, R ^a , R ^b , R ^c , R ^d , R ^e , R ^h , R ¹ and W are all defined above for formula (I) and described in classes and subclasses for formula (I), both individually and in combination.

In some embodiments, the present invention provides compounds of formula (III-a)

or pharmaceutically acceptable salts thereof, wherein R ^a and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (III-b)

or pharmaceutically acceptable salts thereof, wherein R ^a , R ^x and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (III-c)

or pharmaceutically acceptable salts thereof, wherein R ^a and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (IV) ηνΛ (W)^ _Ri f 9's

-NXZ _pe vy X*

R ^a d-NR ^d

R ^b R ^c ^

N (iv) or pharmaceutically acceptable salts thereof, wherein V, X, Y, Z, R ^a , R ^b , R ^c , R ^d , R ^e , R ^h , Ri and W are all defined above for formula (I) and described in classes and subclasses for formula (I), both individually and in combination.

In some embodiments, the present invention provides compounds of formula (IV-a)

or pharmaceutically acceptable salts thereof, wherein R ^a and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

- 4 042925

In some embodiments, the present invention provides compounds of formula (IV-b)

or pharmaceutically acceptable salts thereof, wherein R ^a , R ^x and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments, the present invention provides compounds of formula (IV-c)

or pharmaceutically acceptable salts thereof, wherein R ^a and W are all defined above for formula (I) and are described in classes and subclasses for formula (I), either individually or in combination.

In some embodiments of formulas (I), (II'), (III) and (IV), in each case R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ¹ , Rj, ^Rk and ^Rx are independently selected from hydrogen, halogen and C1- _C6 alkyl.

In some embodiments of formulas (I), (II'), (III) and (IV), R ^a is selected from hydrogen, halogen, and C1-C6 alkyl.

In some embodiments of formulas (I), (II'), (III) and (IV), in each case R ^b , Rc, R ^d , R ^e , R ^f , R ^g , R ^h , R ¹ , R j , R ^k and R ^x each represent hydrogen.

In some embodiments of Formulas (I), (II'), (III) and (IV), R ^a is hydrogen.

In some embodiments of formulas (I), (II'), (III) and (IV), each W is independently selected from halogen, -OR, -CN, optionally substituted C1- _C6 alkyl, optionally substituted _C3 - _C10 cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, acidity and sulfur.

In some embodiments of formulas (I), (II'), (III) and (IV), each W is independently selected from halogen, optionally substituted C1- _C6 alkyl, optionally substituted _C3 - _C10 cycloalkyl, optionally substituted 3 -10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl.

In some embodiments of formulas (I), (II'), (III) and (IV), each W is independently selected from halogen, C1- _C6 alkyl, _C3 -C6 cycloalkyl, optionally substituted 5-6 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl.

In some embodiments of formulas (I), (II'), (III) and (IV), each W is independently selected from chlorine, tert-butyl, cyclohexyl, 2-benzylpiperidinyl, phenyl, 3-cyanophenyl, 3-chlorophenyl, 2phenoxyphenyl and 3-(azetidin-1-ylmethyl)phenyl.

In some embodiments of formulas (I), (II'), (III) and (IV), each R ¹ is independently selected from halogen, -OR, -CN, -NO ₂ , C 1 -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, -(CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl), -(CH ₂ ) _t (310-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -( CH ₂ ) _t (phenyl).

In some embodiments of formulas (I), (II'), (III) and (IV), each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _t (3-6 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _t (phenyl).

In some embodiments of formulas (I), (II'), (III) and (IV), each R ¹ is independently halogen, -OR, -CN and -(CH ₂ ) _t (phenyl).

In some embodiments of Formulas (I), (II'), (III), and (IV), each R is independently selected from hydrogen, C1- _C6 alkyl, and phenyl.

In some embodiments of formulas (I), (II'), (III) and (IV), each R is phenyl.

In some embodiments of formulas (I), (II'), (III), and (IV), each m is 1.

The present invention provides, among other things, chemical structures of formula (I)

or pharmaceutically acceptable salts thereof,

- 5 042925 where V is selected from a chemical bond and CR ^f R ^g ;

X is selected from N and CR ^x ;

Y is selected from a chemical bond, carbonyl (C=O) and CRjR ^k ;

Z is selected from carbonyl (C=O) and CRjR ^k ;

L is -(CH ₂ ) _n -, n=0, 1, 2 or 3, where if n is 2 or 3 then L may optionally be replaced or interrupted by one or two C ₁ -C ₆ -alkyl and/or heteroatoms selected from nitrogen, oxygen and sulfur;

R ^a and R ^x represent hydrogen;

one of R ^b and R ^c is hydrogen, and the other is selected from hydrogen, C ₁ -C ₆ linear or branched alkyl groups and C 1 -C 6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

one of R ^d and R ^e is hydrogen, and the other is selected from hydrogen, C1- _C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with ^R1 ;

one of ^Rf and ^Rg is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with ^R1 , or alternatively, ^Rf and ^Rg are combined with the formation of carbonyl;

one of R ^h and R ¹ is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

one of Rj and ^Rk is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

ring A is selected from 5-10 membered cycloalkyl groups, 5-10 membered heterocycloalkyl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and 5-10 membered heteroaryl groups containing from 1 to 5 heteroatoms , selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one W group;

W is selected from hydrogen, halogen, cyano groups, C ₁ -C ₆ -alkyl groups, C ₁ -C ₆ -alkyl ether groups, 3-10 membered cycloalkyl groups, 3-10 membered heterocycloalkyl groups containing from 1 to 3 heteroatoms, selected from nitrogen, oxygen and sulfur, 6-10 membered aryl and 5-10 membered heteroaryl groups containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one group R ¹ , which may be the same or different; And

R ¹ is independently selected from hydrogen, halogen, hydroxyl groups, cyano groups, amide groups, amino groups, C1-C ₆ alkyl groups, C1-C ₆ alkyl ether groups, C1-C ₆ alkylamino groups, C1-C6 alkyl alcohol groups, C ₃ - C ₆ cycloalkyl groups, S(O) ₂ groups and trifluoromethyl and trifluoromethylether groups, wherein any heteroalkyl group is an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen and sulfur.

In some embodiments of formula (I) above, ring A is selected from

- 6 042925

wherein these groups are optionally replaced by at least one W group.

In some embodiments, W is selected from hydrogen, halogen, cyano groups, C1-G6 alkyl groups, C ₁ -C ₆ alkyl ether groups, 3-10 membered cycloalkyl groups, 3-10 membered heterocycloalkyl groups containing 1 to 3 heteroatoms, selected from nitrogen, oxygen and sulfur, 610-membered aryl groups and 5-10 membered heteroaryl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one R group ¹ , which may be the same or different.

In some embodiments, R ¹ is independently selected from hydrogen, halogen, cyano groups, amide groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkyl ether groups, and trifluoromethyl and trifluoromethyl ether groups.

The present invention provides, among other things, chemical compounds selected from the table below, or pharmaceutically acceptable salts thereof.

Connection number Structure Chemical name 1-1S (8)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-1R V.L D-p (K)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-2S *(8)-8-(5-(tert-butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-2R -'GxM *(K)-8-(5-(tert-butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-3S with (8)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-3R (C)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-4R (C)-8-(5-(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2 carbonitrile 1-4S (8)-8-(5-(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2 carbonitrile

- 7 042925

1-5R (R)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-5S (8)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-6R ^qAaZO (R)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-6S y-AxZ (8)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7R '•'OU^'A (R)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7S (8)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-11R (R)-8-(5 -(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-11S '-yA (8)-8-(5-(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile

- 8 042925

1-12S,R (4aS, 8aR)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12R,S H (4aI,8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12R,R (4aK,8aK)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12S,S (4a8,8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 2-1R ...... ^L r ^J (R)-8-(5-cyclohexylthiazol-2-yl)-4,9dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1S θ0 ' ^r ' (8)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1R oA CIS ’ (R)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 4-lS,S 'Άs H (4a8,8a8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile

- 9 042925

4-lS,R (4aS,8aR)-7-(5-LtHKnoreKcnnTHa3on-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 4-lR,S r-1 ^S \__/ 1 1 (4a^8a8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 5-lR,R Ad-iY (ZaK,7aK)-2-(5-cyclohexylthiazol-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile 5-lS,S (Za8,7a8)-2-(5-cyclohexylthiazol-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile 5-2R,R \ 4 (3aR,7aR)-2-(5-(3cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-carbonitrile 5-2S,S /=\ /=4 \ 4 (3aS,7aS)-2-(5-(3- cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyr idin-5-carbonitrile 6-1R O qA Y H /—\ About N-#\ Cl (C)-8-(5-(tert-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 6-1S 0 a/S YY />Yr 0 N-/ ^λ Cl (8)-8-(5-(tert-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-14S ..... *(8)-9-oxo-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile

- 10 042925

1-14R *(R)-9-oκco-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile „j gu/ ^s \ (R)-8-(5-(τpeτ-bytyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-15S 0 Ν-^Λ / ^N % = | Il y—Z ^s \ (8)-8-(5-(tert-butyl)thiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-113S On ° s-R \=R x , I 1 > Χ'γΖ^ν *(8)-9-oxo-8-(5-(2-phenoxyphenyl)thiazol-2-yl)octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-113R .. *(R)-9-okco-8-(5-(2phenoxyphenyl)thiazol-2-yl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile 1-114R / 0 (R)-9-oκco-8-(5-(2-φenoκciφenyl)1H-pyrazol-3-yl)-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-114S P ° ^{n n} \ ^Z=\ II II Vz \ X^Z-PP^w LJ (8)-9-oxo-8-(5-(2-phenoxy-phenyl)1H-pyrazol-3-yl)-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile

- 11 042925

1-115R ABOUT / (R)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-115S \DlK) (S)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-116R O N—P C.I. (K)-8-(5-(tert-butyl)-4-chloro-thiazol2-yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-116S Argu- (8)-8-(5-(tert-butyl)-4-chloro-thiazol-2yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-117R ⁰ Ν- λ у---—. χνΧ) (R)-8-(5-cyclohexylthiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-117S O Ν-'-'-λ ,-- 1 ϊ 5 XX TG ^s \___/ (8)-8-(5-cyclohexylthiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118R,S R G ^Ν 1 ( Υ Υ / ο nJ (R)-8-(5-((S)-2-benzylπpipipiridin-1 yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118R,R ο / \ Υ Υ У-ч / ο nJ \ ^J (R)-8-(5-((R)-2-benzylπpipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118S,S Ρ ί ^Ν 1 4 / \ Υ Υ /Ύ / (8)-8-(5-((8)-2-benzylpiperidin-1yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118S,R ο /\ X Υ Υ У-ч J ο ν/ ⁷ ρ—' (S)-8-(5-((R)-2-benzylπpipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile

It should be understood that, unless otherwise indicated, it is intended that throughout the present invention, reference to compounds of formula (I) also includes formulas (II'-a), (II'-b), (II'-c), (II'-d), (II'-e), (II'-g), (III), (III-a), (III-b), (III-c), (IV), (IV- a), (IV-b) and (IV-c) and the species of compounds of such formulas described in the invention.

It should be understood that, unless otherwise indicated, throughout the present invention, reference to chemical structure is intended to include, for example, compounds.

It should be borne in mind that unless otherwise specified, when one or more substituents are listed for a particular variable, then this form of listing includes one, two, three, four or more substituents, unless this conflicts with the valence requirements.

The compounds described in the invention may contain optionally substituted moieties. Generally, the term substituted, whether optionally preceded by a term or not, means that one or more hydrogens of the designated moiety have been replaced by a suitable substituent. Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substitutable position in the group, and when more than one position in any given structure may be substituted with more than one substituent selected from

- 12 042925 of the specified group, the substituent in each position can be either the same or different. It is preferred that the combinations of substituents provided by this invention are combinations that result in the formation of stable or chemically feasible compounds. As used herein, the term stable refers to compounds that do not change substantially when exposed to the conditions under which they are produced, detected, and, in particular embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

In some embodiments, the present invention provides compounds of formula (I) disclosed herein that have an IC ₅₀ value of approximately 1 μmol or less, as determined by the Ubiquitin-Rhodamine 110 USP30 assay described in Example A of the invention. In some embodiments, The present invention provides compounds of formula (I) having one or more of the following characteristics as determined by testing in Example A: (i) IC ₅₀ value <10 μM and >1 μM; (ii) IC5 ₀ value <1 µM and > 0.1 µM; or (iii) IC ₅₀ value <0.1 μM. In some embodiments, compounds of formula (I) have one or both of the following characteristics as determined when tested in Example A: (i) _IC50 value <1 μM and >0.1 μM; or (ii) IC ₅₀ value <0.1 μM. In some embodiments, compounds of formula (I) have an IC ₅₀ value of <0.1 μM as determined when tested in Example A.

As used herein, the term aliphatic or aliphatic group means a linear (i.e. straight-chain) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, or a monocyclic, bicyclic or polycyclic hydrocarbon that is fully saturated or which contains one or more unsaturation units, but which is not aromatic (also called a cycloaliphatic or cycloalkyl carbocycle in the invention), which has a single point of attachment to the rest of the molecule. In some embodiments, the aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in some embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and combinations thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term alkyl has the meaning generally accepted in chemistry and can include saturated aliphatic groups, including linear alkyl groups and branched alkyl groups.

The term heteroalkyl has a common chemical meaning and refers to the alkyl groups described herein in which one or more carbon atoms are replaced by a heteroatom (eg, oxygen, nitrogen, sulfur and other similar heteroatoms). Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)- and alkyl-substituted amino group and so on.

The term halogen refers to F, Cl, Br or I.

The terms cycloalkyl and heterocycloalkyl, as used herein, are intended to designate monocyclic or polycyclic rings. The group may be fused (eg decalin) or bridged (eg norbornane). In addition, there are no delocalized πelectrons (aromaticity) shared by all carbon atoms or heteroatoms of the ring.

A cycloalkyl ring refers to a saturated aliphatic monocyclic, bicyclic or polycyclic ring system having from 3 to 14 ring atoms. In some embodiments, the cycloalkyl ring has 3-10 carbon atoms in its ring structure, where such rings are monocyclic or bicyclic, and optionally 3, 4, 5, 6 or 7 carbons in the ring structure. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl and adamantyl.

As used herein, the terms heterocycle, heterocyclyl and heterocyclic ring are used interchangeably and refer to a stable 3-14 membered monocyclic or 7-14 membered bicyclic or polycyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more preferably from one to three heteroatoms. When applied to the ring atom of a heterocycle, the term nitrogen includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or +NR (as in N

- 13 042925 substituted pyrrolidinyl). The heterocyclic ring may be attached to its side group on any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinil, morpholinil and quinuclidinil. The terms heterocycle, heterocyclyl and heterocyclic ring also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.

As used herein, the term heterocycloalkyl refers to a saturated, heterocyclic, monocyclic, bicyclic or polycyclic ring having from 3 to 14 ring atoms. In some embodiments, the heterocycloalkyl ring has 3-10 ring atoms in the ring structure, where such rings are monocyclic or bicyclic, and optionally have 3, 4, 5, 6, or 7 ring atoms in the ring structure.

As used herein, the terms aryl and heteroaryl refer to cyclic, aromatic groups, including monocyclic or bicyclic groups. When two aromatic rings are contained (bicyclic), the aromatic rings of aryl or heteroaryl groups may be combined at one point (eg, biphenyl) or fused (eg, naphthyl).

The term aryl refers to monocyclic, bicyclic or polycyclic ring systems having a total of five to fourteen ring atoms, where at least one ring in the system is aromatic, and where each ring in the system contains from 3 to 7 ring atoms. The term aryl may be used interchangeably with the term aryl ring. In some embodiments of the present invention, aryl refers to an aromatic ring system that includes, but is not limited to, phenyl, naphthyl, anthracyl, and other similar aryls that may bear one or more substituents. Also included within the scope of the term aryl as used herein is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl and other similar groups.

The term heteroaryl refers to monocyclic, bicyclic or polycyclic groups having 5 to 14 ring atoms (eg 5 to 10 ring atoms), preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons distributed in a cyclic structure, and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteri dinil. Also included within the scope of the term heteroaryl as used herein are groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazoluyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothia zinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [2,3-b]-1,4-oxazin-3(4H)-one. The term heteroaryl may be used interchangeably with the terms heteroaryl ring, heteroaryl group, or heteroaromatic, any of which includes rings that are optionally substituted.

As used herein, the term unsaturated means that the moiety has one or more units of unsaturation. Accordingly, as used herein, the term partially unsaturated refers to a ring moiety that includes at least one double or triple bond. The term partially unsaturated is intended to include rings having multiple sites of unsaturation, but does not include aryl or heteroaryl moieties as described herein.

Pharmaceutical forms of the chemical structures disclosed herein may include pharmaceutically acceptable salts, solvates, and other similar forms. Unless otherwise stated, it is intended that all pharmaceutical forms, such as all tautomeric forms and stereoisomers, be part of the present invention. Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (eg, enantiomeric, diastereoisomeric, and geometric (or conformational)) forms of the structure, eg, R and S configurations for each stereocenter. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereoisomeric and geometric (or conformational) mixtures of the compounds of the present invention are included within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

- 14 042925

If the stereochemistry is not indicated with an asterisk (*), then the stereochemistry specified in the invention is assigned arbitrarily. For example, in some cases, Table B lists one or more stereoisomers of a compound and, unless otherwise indicated, represents each stereoisomer individually and/or each enantiomer or diastereomer thereof, and/or a mixture thereof. For example, Table B shows (K)-8-(5-cyclohexylthiazol-2-yl)-4,9-dioxoocta-hydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile, and it follows that the present invention also includes (S)-8-(5-cyclohexylthiazol-2yl)-4,9-dioxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile, as well as a mixture thereof. In some embodiments, stereochemistry as used herein refers to the relative stereochemical orientation in each molecule, which is not necessarily the same as absolute stereochemistry.

In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures presented in which the hydrogen is replaced by deuterium or tritium, or the carbon is replaced by ¹³ C- or ¹⁴ C-rich carbon are within the scope of this invention.

The compounds of formula (I) can form salts, which are also included within the scope of this invention. It is understood that reference in the invention to a compound of formula (I) includes reference to its salts unless otherwise indicated. Pharmaceutically acceptable ones are well known. For example, pharmaceutically acceptable salts are described in detail in S.M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977).

Compositions of the described compounds

Another aspect of the invention relates to pharmaceutical compositions containing a chemical structure selected from the compounds of formula (I) and pharmaceutical forms thereof, together with a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier used in the invention refers to pharmaceutical excipients, for example, pharmaceutically, physiologically acceptable organic or inorganic carrier substances suitable for enteral or parenteral use, which do not have a harmful chemical effect on the active substance. The pharmaceutically acceptable carrier may further include additional excipients, diluents and/or surfactants and the like. The compounds described in the invention for USP30 inhibition may be combined with pharmaceutically acceptable excipients suitable for the intended route of administration to humans or animals. Excipients may be selected to formulate a dosage form suitable for the intended route of administration, including oral or parenteral dosage forms.

In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the provided pharmaceutical compositions may be in unit dose dosage form (eg, capsule, tablet, or other similar form). In some embodiments, the pharmaceutical compositions described herein may be formulated in an oral dosage form. In some embodiments, the pharmaceutical composition is orally administered in any dosage form suitable for oral administration. In some embodiments, the oral dosage form includes one or more excipients, disintegrants, lubricants, glidants, release agents, and/or antistatic agents.

Methods of using the compounds disclosed in the invention

The present invention provides the use of compounds of formula (I). The compounds of formula (I) are useful in medicine. For example, the compounds and compositions described herein are USP30 inhibitors.

The USP30 inhibitory compounds provided herein (e.g., compounds of formula (I)) are used to inhibit USP30 in a cellular or other living system, including the development of pharmaceutical compositions for the therapeutically effective treatment of human disease or disease symptoms associated with USP30 activity. As used herein, the term therapeutically effective refers to the use of an active compound or drug (e.g., a USP30 inhibitory compound of formula (I) and/or a USP30 inhibitory compound having an IC ₅₀ value of less than about 1 μmol or less, as determined by assay Ubiquitin-Rhodamine 110 for USP30 described in the invention in Example A), which achieves a desired and/or therapeutic biological or therapeutic response or effect in a cell, tissue, system, animal, individual or human, including any one or more of the following: (1) preventing a disease (e.g., preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder, but who is not yet experiencing or has not yet exhibited pathology or symptoms of the disease), (2 ) inhibition of disease progression (by

- 15 042925 example, slowing or stopping the progression of a disease or symptoms of a disease, condition or disorder in an individual who is experiencing or exhibiting pathology or symptoms of a disease, condition or disorder, including stopping the further development of pathology and/or symptoms), or ( 3) alleviation of a disease or its symptoms (for example, a decrease in the frequency or intensity of a symptom associated with a disease, condition or disorder in an individual who experiences or exhibits pathology or symptoms of the disease, condition or disorder, including regression of the pathology and/or symptoms ). The USP30 inhibitory compounds disclosed herein (eg, compounds of formula (I)) may be used in an amount effective to achieve the desired effect (eg, a therapeutically effective amount). In some embodiments, the therapeutically effective amount is administered in a single dose; in some embodiments, multiple administrations of single doses are required to administer a therapeutically effective amount.

Without being bound by any particular theory, it is believed that the chemical structures of formula (I) and pharmaceutical forms thereof may be used to inhibit USP30. This inhibition may result in practical treatment of symptoms and/or underlying causes of diseases or conditions for which USP30 inhibition is necessary. For example, USP30 inhibitors may be used to treat neurodegenerative and neurological diseases or conditions involving mitochondrial dysfunction, such as Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that affects more than 10 million people worldwide, with 60,000 new cases diagnosed each year in the United States alone (Parkinson's Disease Foundation, www.pdf.org). Parkinson's disease is characterized by loss of dopaminergic neurons in the substantia nigra. Although the exact mechanism of neuronal loss is not yet fully understood, a growing body of evidence reveals a relationship between mitochondrial dysfunction and dopaminergic neuron vulnerability.

Parkin (E3 ubiquitin ligase) and PINK1 (kinase) are key regulators of mitophagy. In healthy mitochondria, PINK1 localization to the mitochondrial outer membrane (MOM) and cytosolic exposure are limited by rapid import to the mitochondrial inner membrane (MIM). Once localized to the MIM, PINK1 is processed by several proteases, such as presenilin-associated rhomboid-like protease (PARL), to produce a truncated version of PINK1, which is subsequently degraded by the proteasome (Meissner et al., Autophagy. 2015, 11(9), 1484-1498) . Upon mitochondrial depolarization or dysfunction, PINK1 accumulates in the mitochondrial outer membrane (MOM), subjecting Parkin to recruitment and activation through PINK1-dependent phosphorylation of both ubiquitin and Parkin. Consequently, activated Parkin ubiquitinates MOM proteins such as TOMM20 to trigger mitophagy (Pickrell et al., Neuron.2015, 85(2), 257-273).

USP30 is integrated into the MOM with its DUB catalytic domain oriented toward the cytosol and has been shown to antagonize Parkin-mediated ubiquitination of common substrates, hence counteracting Parkin-mediated mitophagy. Genetic silencing of USP30 results in increased ubiquitination of certain Parkin substrates, followed by increased mitophagy. In model organisms, USP30 depletion is able to rescue mitophagy defects caused by pathogenic Parkin mutations and restore mitochondrial morphology and function, as well as dopamine levels. (Nakamura, et al., Mol Biol Cell. 2008, 19(5), 1903-1911; Bingol, et al., Nature 2014, 510(7505): 370-5). Therefore, the present invention concludes that inhibition of USP30 using the compound described herein may represent a new standard treatment for Parkinson's disease by promoting mitochondrial turnover.

Accordingly, the present invention relates to the development of methods for treating a disease or disorder associated with USP30, comprising administering to a patient suffering from at least one of said diseases or disorders a chemical structure of formula (I) and/or pharmaceutical forms thereof, optionally in form of a pharmaceutical composition. The disclosed chemical entities may be administered in effective amounts to treat or prevent the disorder and/or prevent its development in subjects. Methods of treating a disease or disorder with a compound known to inhibit USP30 with an IC ₅₀ value of less than about 1 μM as determined by the Ubiquitin-Rhodamine 110 assay for USP30 described in Example A of the invention may include administering to a patient to the person in need thereof, a therapeutically effective amount of a pharmaceutical composition containing a compound of formula (I). In some embodiments, the pharmaceutical composition contains a USP30-inhibiting compound of formula (I) and/or a USP30-inhibiting compound having an IC ₅₀ value of less than about 1 μmol as determined by the Ubiquitin-Rhodamine 110 assay for USP30 described in the invention by Example A.

In some embodiments, the present invention provides a method of inhibiting USP30 in a human, comprising administering a therapeutically effective amount of (i) disclosed in

- 16 042925 invention of a compound, or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition containing a compound disclosed in the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Methods of treating a disease, disorder, or condition associated with ubiquitin-specific peptidase 30 (eg, by inhibiting USP30) may include administering to a subject in need thereof a therapeutically effective amount of (i) a compound of the invention or a pharmaceutically acceptable salt thereof, or (ii) a pharmaceutical composition containing a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In some embodiments, a method of treating a disease associated with modulation (eg, inhibition) of USP30 includes administering a therapeutically effective amount of a compound of the invention.

In some embodiments, a method of treating a neurodegenerative or neurological disease, disorder or condition comprises administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method of treating a disease, disorder, or condition associated with mitochondrial dysfunction includes administering a therapeutically effective amount of a compound disclosed herein. In some embodiments, a method of treating Parkinson's disease includes administering a therapeutically effective amount of a compound disclosed herein.

Methods for the synthesis of the compounds disclosed in the invention

The compounds disclosed in the invention can be prepared by methods well known in the field of organic synthesis, which are partially represented in the following synthesis schemes. It is apparent from the schemes described below that protecting groups are used for sensitive or reactive groups when necessary based on general principles and process chemistry. To install protective groups, standard methods of organic synthesis are used (T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999). These groups are removed at an appropriate stage in the synthesis of the compound using methods that are well known to those skilled in the art. The choice of processes, as well as the reaction conditions and the order of their implementation, should lead to the production of compounds of formula (I).

Those skilled in the art will appreciate those cases where a stereocenter is present in the structures of compounds of formula (I). Accordingly, the present invention includes all possible stereoisomers (unless otherwise indicated during the synthesis), and includes not only racemic compounds, but also individual enantiomers and/or diastereomers.

Receiving connections.

Chemical structures of formula (I) can be obtained by various methods, including standard methods of chemical transformations. Suitable synthetic routes are depicted in the diagrams below.

For example, the compounds of the present invention can be synthesized using the methods described below, as well as methods known in the field of organic synthesis chemistry, or variations of these methods that are well known to specialists in this field.

By way of non-limiting example, compounds of formula (I) may be considered according to the following general formula A'-B':

A' B' where the corresponding fragment A' or its precursor can be added using the methods presented in the invention to the corresponding fragment B' or its precursor to form compounds of formula (I).

As indicated below, in some embodiments, the compounds of formula A'-B' are compounds of formula I-i and/or I-ii

I-i I-ii where all options for A’ and B’ are interchangeable

- 17 042925

The compounds described in the invention can be obtained from commercially produced starting materials or the starting materials can be synthesized using known organic, inorganic and/or enzymatic processes. For example, starting materials B' can be supplied by manufacturers or synthesized by methods presented in the invention. In some embodiments, B' may then be coupled to A' according to several syntheses, such as the following non-limiting examples of syntheses.

General scheme 1

A protected group B'-a (such as intermediate B'-1), where PG is a suitable nitrogen protecting group (eg, a Boc group), can be attached to a group A'a (such as 2-bromo-5- cyclohexylthiazole), where LG represents a suitable leaving group (eg halogen, -OTf, etc.), by performing a cross-coupling reaction using a suitable metal catalyst (eg palladium catalyst) and base (eg CS2CO3). The protecting group can then be removed by performing an appropriate deprotection reaction (eg, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid), and the resulting amine can be functionalized with a nitrile group in the presence of a base (eg, NaHCO ₃ ) and a cyanidation reagent (for example, BrCN).

Additional addition reaction procedures are presented below.

General scheme 2

B'-b can be attached to a group A'-a, where LG represents a suitable leaving group (e.g. halogen, -OTf, etc.) by performing a cross-coupling reaction using a suitable metal catalyst (e.g. palladium catalyst) . The resulting compound can then be reduced in the presence of H ₂ or other suitable source of hydrogen and a suitable metal catalyst (eg Pd(OH) ₂ ). The resulting amine can then be functionalized with a nitrile group in the presence of a base (eg NaHCO3) and a cyanidation reagent (eg BrCN).

General scheme 3

- 18 042925

A protected group B'-a, where PG is a suitable nitrogen protecting group (eg a Boc group), can be attached to a group A'-a, where LG is a suitable leaving group (eg halogen, -OTf, etc. hereinafter) by performing a cross-coupling reaction using a suitable metal catalyst (eg copper catalyst) and base (eg K ₃ PO ₄ ). The protecting group can then be removed by performing an appropriate deprotection reaction (eg, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid), and the resulting amine can be functionalized with a nitrile group in the presence of a base (eg, NaHCO ₃ ) and a cyanidation reagent (for example, BrCN).

General scheme 4

A protected group B'-a, where PG is a suitable nitrogen protecting group (e.g., a Boc group), can be attached to a group A'-b, where each LG is an independently suitable leaving group (e.g., halogen, -OTf, and so on) by performing a displacement reaction in the presence of a base (eg DIPEA). The resulting product can be reacted with a W group (particularly when W is an aryl or heteroaryl ring as defined herein) where E is a suitable electrophilic group (eg -B(OH) ₂ ) by performing a cross- combination in the presence of a suitable metal catalyst (eg palladium catalyst) and a base (eg K3PO4). The protecting group can then be removed by performing an appropriate deprotection reaction (eg, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid), and the resulting amine can be functionalized with a nitrile group in the presence of a base (eg, NaHCO ₃ ) and a cyanidation reagent (for example, BrCN).

In some embodiments, B' is obtained after reacting with A' according to the same synthesis line. Non-limiting examples include the following circuits.

General scheme 5

Amino acid 1 (for example, (R)-2-(((benzyloxy)-carbonyl)amino)-3-((tert-butoxyarbonyl)amino)propanoic acid) can be attached to an amine (for example, the A'-c group above ) by using a standard coupling reagent (eg HATU) and a base (eg DIEA) in a suitable solvent and a protecting group 1 (ie PG ¹ ) such as a Boc group, which can then be removed by performing an appropriate deprotection reaction groups (for example, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid or hydrochloric acid) in a suitable solvent. The resulting amine can be reacted with a suitable carboxylic acid derivative (eg, methyl-2-bromoacetate derivative), where each LG represents an independently leaving group (eg, halogen, -OTf, -OCH3, etc.). The protecting group 2 (ie, PG ² ), such as the Cbz group, is removed by performing an appropriate deprotection reaction (for example, the Cbz group can be removed in the presence of H2 and a suitable metal catalyst such as Pd/C), followed by in situ cyclization into a piperazinone ring. The piperazinone ring can be protected under suitable conditions with a protecting group 3 (i.e., PG ³ ), such as a Boc group, and then bis-alkylated with an appropriate electrophile (e.g., ethane-1,2-diyl-bis(trifluoromethanesulfonate) )), where each LG represents an independently leaving group (eg, halogen, -OTf, and so on), to form a bicyclic ring configuration. Then, the protecting group 3 can be removed by performing an appropriate deprotection reaction (for example, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid), and the resulting amine can be functionalized with a nitrile group in the presence of a base (for example, NaHCO3) and cyanidation reagent (for example, BrCN).

- 19 042925

An additional method for producing B' after reacting with A' is presented below.

General scheme 6

(I)

Piperazine derivative 1 can be protected with a suitable nitrogen protecting group (ie, PG2) under appropriate conditions (eg, the Cbz protecting group can be established with CbzCl). A bicycle is then formed in the presence of a suitable electrophile (eg 2-chloroacetyl chloride), where each LG represents an independently leaving group (eg halogen, -OTf, -OCH3, etc.), then a base (eg NaH) is added. Protecting group 2 (i.e., PG2) is removed by performing an appropriate deprotection reaction (e.g., the Cbz group can be removed in the presence of H ₂ and a suitable metal catalyst such as Pd/C), then reacting with the A'-a group, where LG represents a suitable leaving group (eg halogen, -OTf, etc.) by performing a cross-coupling reaction using a suitable metal catalyst (eg palladium catalyst) and base (eg Cs ₂ CO ₃ ). Then, the protecting group 1 (ie, PG ¹ ) can be removed by performing an appropriate deprotection reaction (eg, the Boc protecting group can be removed in the presence of an acid such as trifluoroacetic acid), and the resulting amine can be functionalized with a nitrile group in the presence of a base (eg NaHCO ₃ ) and a cyanidation reagent (eg BrCN).

Example Embodiments

The following numbered embodiments, which are not intended to be limiting of the invention, are examples of specific aspects of the present invention.

1. Compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein X is selected from N and CR ^x ;

V, Y and Z are selected from (i), (ii) or (iii):

(i) V represents C(O); Y choose C(O) and CR ^j R ^k ; and Z is selected from C(O) and CR ^j R ^k ;

(ii) V is selected from the chemical bond, C(O) and CR ^f R ^g ; Y represents C(O); and Z is selected from C(O) and CR ^j R ^k ; or (iii) V is selected from the chemical bond, C(O) and CR ^f R ^g ; Y is selected from C(O) and CR ^j R ^k ; and Z represents C(O);

L represents -(CH ₂ ) _n -;

n is 0, 1 or 2, wherein each methylene unit in L is optionally replaced by one C ₁ -C ₆ alkyl, and where if n is 2 then one methylene unit in L is optionally replaced by oxygen;

in each case R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , Ri, R ^j , R ^k and R ^x are independently selected from hydrogen, halogen and C ₁ -C ₆ - alkyl;

ring A is selected from C ₃ -C ₁₀ -cycloalkyl, 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and 5-10 membered heteroaryl containing from 1 to 3 heteroatoms, selected from nitrogen, oxygen and sulfur, wherein ring A is optionally substituted with one or more W;

each W is independently selected from halogen, -OR, -CN, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected of nitrogen, oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where the optionally substituted W group may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN, -NO ₂ , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl,

- 20 042925

-(CH ₂ ) _t (C ₃ -C ₁₀ -cycloalkyl), -(CH ₂ ) _w (3-10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl);

each R is independently selected from hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl and phenyl; and each m is independently 0 or 1.

2. The compound of embodiment 1, wherein Y is selected from C(O) and CRjR ^k ;

n represents 0;

R ^a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl;

^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh ,} Ri, Rj, ^Rk and ^Rx are each hydrogen;

ring A is a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W;

each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl, wherein the optionally substituted W group may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _m (3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ )t (C ₆ aryla);

each R represents phenyl and each m represents 1.

3. The compound of embodiment 1 or 2, wherein V is selected from C(O) and CR ^f R ^g ; X represents N;

Y represents C(O);

n represents 0;

R ^a represents hydrogen;

^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh , R1} , Rj, ^Rk and ^Rx are each hydrogen;

ring A is a 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W;

each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl, wherein the optionally substituted W group may be substituted by one or more R ¹ ;

each R ¹ is independently selected from halogen, -OR, -CN and -(CH ₂ ) _m (phenyl);

each R represents phenyl and each m represents 1.

4. The compound of any one of embodiments 1-3, wherein L is selected from -(CH ₂ ) ₀ -, -CH2-, -CH2CH2- and -CH2CH(CH3)-.

5. The connection according to any one of embodiments 1-4, where n is 0.

6. The compound according to any one of embodiments 1-5, where the compound has formula (II'-a) (Ring) - - h

N (1G-a) or a pharmaceutically acceptable salt thereof.

7. The compound of any one of embodiments 1-5, wherein the compound has the formula

or a pharmaceutically acceptable salt thereof.

- 21 042925

8. The compound of any one of embodiments 1-5, wherein the compound has formula (II'-c)

or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of embodiments 1-5, wherein the compound has formula (II'-d)

or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of embodiments 1-5, where the compound has formula (II'-e)

or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of embodiments 1-5, where the compound has formula (II'-g)

or a pharmaceutically acceptable salt thereof.

12. The compound of any one of embodiments 4-11, wherein ring A is selected from C ₃ -C ₁₀ -cycloalkyl, 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and A 5 to 10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein ring A is optionally substituted with one or more W.

13. The compound of any one of embodiments 1, 2 and 4-12, wherein ring A is an optionally substituted 5-6 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

14. The compound of any one of embodiments 1-13, wherein ring A is an optionally substituted 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

15. The compound of any one of embodiments 1-14, wherein ring A is an optionally substituted thiazolyl or pyrazolyl.

16. The compound of any one of embodiments 1-15, wherein the compound has the formula (ΠΙ)

or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of embodiments 1-6 and 12-16, where the compound has the formula (III-a)

or a pharmaceutically acceptable salt thereof.

- 22 042925

18. The compound of any one of embodiments 1-5, 7 and 12-16, wherein the compound has formula (III-b)

or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of embodiments 1-5, 8 and 12-16, where the compound has formula (III-c) < ^N /—\ /°

L

R ^a N \\

N (sh-s) or a pharmaceutically acceptable salt thereof.

20. The compound according to any one of embodiments 1-15, where the compound has formula ^(IV)

or a pharmaceutically acceptable salt thereof.

21. The compound according to any one of embodiments 1-6, 12-15 and 20, where the compound has formula (IV-a)

or a pharmaceutically acceptable salt thereof.

22. The compound of any one of embodiments 1-5, 7, 12-15 and 20, where the compound has formula (IV-b) (Wh-2 o ^; Q ^v n

N(iv-b) or a pharmaceutically acceptable salt thereof.

23. The compound of any one of embodiments 1-5, 8, 12-15 and 20, wherein the compound has formula (IV-c)(W),^ A-N

N(iv-c) or a pharmaceutically acceptable salt thereof.

24. The connection as in any one of embodiments 4-23, wherein in each case Ra, R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , Ri, R', R ^k and R ^x independently selected from hydrogen, halogen and C ₁ -C ₆ -alkyl.

25. The compound of any one of embodiments 1, 2 and 4-23, wherein Ra is selected from hydrogen, halogen and C ₁ -C ₆ alkyl.

26. The connection of any one of embodiments 1-25, wherein in each case R ^b , Rc, R ^d , R ^e , R ^f , R ^g , R ^h , Ri, R', R ^k and R ^x each represent hydrogen.

27. The compound of any one of embodiments 1-26, wherein Ra is hydrogen.

28. The compound of any one of embodiments 4-27, wherein each W is independently selected from halogen, -OR, -CN, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3 -10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.

29. The compound of any one of embodiments 1-28, wherein each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted

- 23 042925

C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl.

30. The compound of any one of embodiments 1-29, wherein each W is independently selected from halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, optionally substituted 5-6 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl.

31. The compound of any one of embodiments 1-30, wherein each W is independently selected from chlorine, tert-butyl, cyclohexyl, 2-benzylpiperidinyl, phenyl, 3-cyanophenyl, 3-chlorophenyl, 2-phenoxyphenyl, and 3-(azetidine-1- ylmethyl)phenyl.

32. The compound of any one of embodiments 4-31, wherein each R ¹ is independently selected from halogen, -OR, -CN, -NO ₂ , O ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, -( CH ₂ ) _m (C ₃ -C ₁₀ -cycloalkyl), -(CH ₂ ) _m (3-10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl).

33. The compound of any one of embodiments 1 and 4-32, wherein each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _m (3-6 membered heterocyclyl containing from 1 to 3 heteroatoms , selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl).

34. The compound of any one of embodiments 1-33, wherein each R ¹ is independently halogen, -OR, -CN, and -(CH ₂ ) _m (phenyl).

35. The compound of any one of embodiments 1 and 4-34, wherein each R is independently selected from hydrogen, C ₁ -C ₆ alkyl, and phenyl.

36. The compound of any one of embodiments 1-35, wherein each R is phenyl.

37. The connection as in any one of embodiments 1-36, wherein each m is 1.

38. Compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein V is selected from a chemical bond and CR ^f R ^g ;

X is selected from N and CR ^x ;

Y is selected from a chemical bond, carbonyl (C=O) and CRjR ^k ;

Z is selected from carbonyl (C=O) and CRjR ^k ;

L is -(CH ₂ ) _n -, n=0, 1, 2 or 3, where if n is 2 or 3 then L may optionally be replaced or interrupted by one or two C ₁ -C ₆ -alkyl and/or heteroatoms selected from nitrogen, oxygen and sulfur;

R ^a and R ^x represent hydrogen;

one of R ^b and R ^c is hydrogen, and the other is selected from hydrogen, C ₁ -C ₆ linear or branched alkyl groups and C 1 -C ₆ linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

one of R ^d and R ^e is hydrogen, and the other is selected from hydrogen, C1- _C6 linear or branched alkyl groups and C1- _C6 linear or branched heteroalkyl groups, optionally substituted with ^R1 ;

one of ^Rf and ^Rg is hydrogen, and the other is selected from hydrogen, C1- _C6 linear or branched alkyl groups and C1- _C6 linear or branched heteroalkyl groups, optionally substituted with ^R1 , or alternatively ^Rf and R ^g are combined to form carbonyl;

one of R ^h and R ⁱ is hydrogen, and the other is selected from hydrogen, C 1 -C ₆ linear or branched alkyl groups and C 1 -C ₆ linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

one of Rj and ^Rk is hydrogen, and the other is selected from hydrogen, C _g C ₆ linear or branched alkyl groups and C 1 -C ₆ linear or branched heteroalkyl groups, optionally substituted with R ¹ ;

ring A is selected from 5-10 membered cycloalkyl groups, 5-10 membered heterocycloalkyl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and 5-10 membered heteroaryl groups containing from 1 to 5 heteroatoms , selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one W group;

W is selected from hydrogen, halogen, cyano groups, C1- _C6 alkyl groups, C1- _C6 alkylether groups, 3-10 membered cycloalkyl groups, 3-10 membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, 6-10-membered aryl and 5-10-membered he

- 24 042925 teroaryl groups containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one R ¹ group, which may be the same or different; And

R ¹ is independently selected from hydrogen, halogen, hydroxyl groups, cyano groups, amide groups, amino groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkyl ether groups, C ₁ -C ₆ alkylamino groups, C1-C6 alkyl alcohol groups, C3- _C6 cycloalkyl groups, S(O) ₂ groups and trifluoromethyl and trifluoromethylether groups, wherein any heteroalkyl group is an alkyl group in which one or more carbon atoms have been replaced by a heteroatom selected from nitrogen, oxygen and sulfur.

39. The connection of embodiment 38, wherein ring A is selected from

wherein these groups are optionally replaced by at least one W group.

40. The compound of embodiment 38 or 39, wherein W is selected from hydrogen, halogen, cyano groups, C1- _C6 alkyl groups, C1- _C6 alkylether groups, 3-10 membered cycloalkyl groups, 310 membered heterocycloalkyl groups, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups and 5-10 membered heteroaryl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the groups are unsubstituted or substituted by at least one R ¹ group, which may be the same or different.

41. The compound of any one of embodiments 38-40, wherein R ¹ is independently selected from hydrogen, halogen, cyano groups, amide groups, C1- _C6 alkyl groups, C1- _C6 alkylether groups, and trifluoromethyl and trifluoromethylether groups.

- 25 042925

78. Connection selected from

Connection number Structure Chemical name 1-1S hoo-o (8)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-1R wow ^)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-2S xEtUx\ _α *(8)-8-(5-(tert-butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-2R χΑγνΗ *^)-8-(5-(tert-butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-3S (8)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-3R ^)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-4R (R)-8-(5-(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-4S uuU^' (8)-8-(5-(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile

- 26 042925

1-5R (R)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-5S (8)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-6R / ... L XU <\ C O (R)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-6S ^Nv oOC (8)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7R nO (R)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7S nO' ⁰ ' (8)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-11R (R)-8-(5 -(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-11S .QAACd (8)-8-(5-(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile

- 27 042925

1-12S,R 00 (4aS, 8aR)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12R,S v 0° (4aD,8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12R,R H (4aK,8aK)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12S,S '04 (4a8,8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 2-1R .......1....J (R)-8-(5-cyclohexylthiazol-2-yl)-4,9dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1S /0G (8)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1R gL vA' ⁴ · (R)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 4-lS,S TO 0 ^X N ^X \^y H (4a8,8a8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile

- 28 042925

4-lS,R 4 γ ΤΓ S \__/ (4aS,8aR)-7-(5-ijHKnoreKCHnTHa3on-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 4-lR,S a = xcr Г-Ι ^S \__/ 1 i ⁿ 1 (4a^8a8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 5-lR,R (3aR,7aR)-2-(5-ijHiaioreKcmrrHa3Cui-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile 5-lS,S (Za8,7a8)-2-(5-cyclohexylthiazol-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile 5-2R,R r. \ h (3aR,7aR)-2-(5-(3cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-carbonitrile 5-2S,S 4'ό ABOUT (3aS,7aS)-2-(5-(3- cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyr idin-5-carbonitrile 6-1R O ud if if z—\ About N-#\ Cl (C)-8-(5-(tert-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 6-1S 0 and I S/ П n )r\ 0 N-A\ Cl (8)-8-(5-(tert-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-14S AqXXPO *(8)-9-oxo-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile

- 29 042925

1-14R *(K)-9-oxo-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile O N- λ / i 1 ) AG ^hT ^S \ (K)-8-(5-(tert-butyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-15S ⁰ Ν-^Λ / ^N = 11 11 V-Ύ—- ^s \ (8)-8-(5-(tert-butyl)thiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-113S . 1 AE *(8)-9-oxo-8-(5-(2-phenoxyphenyl)thiazol-2-yl)octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-113R For ΆγΟ ' *(R)-9-okco-8-(5-(2- phenoxyphenyl)thiazol-2-yl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile 1-114R /0 (C)-9-oxo-8-(5-(2-phenoxyphenyl)1H-pyrazol-3-yl)-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-114S ABOUT ο N—¥ (8)-9-oxo-8-(5-(2-phenoxy-phenyl)1H-pyrazol-3-yl)-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile

- 30 042925

1-115R A.T> (R)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-115S 1 D A Y V/ (S)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-116R ^N N-, z\ // \ Cl (R)-8-(5-(τpeτ-bytyl)-4-chloro-thiazol2-yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-116S Ύ ,s/ Cl (8)-8-(5-(tert-butyl)-4-chloro-thiazol-2yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile N-- (R)-8-(5-cyclohexylthiazol-2-yl)-9a- 1-117R γΑ -N J JL methyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazine-2carbonitrile 0 uu'd (8)-8-(5-cyclohexylthiazol-2-yl)-9a- 1-117S Af ^X N J methyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazine-2carbonitrile 1-118R,S nA 0 ^S 4 A P y-N__/ (R)-8-(5-((S)-2-benzylπpipiridin-1 yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118R,R N _x nA ^N^ ABOUT nY ABOUT N (R)-8-(5-((R)-2-benzylπpipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118S,S nA D O A P )—__/ (8)-8-(5-((8)-2-benzylpiperidin-1yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118S,R .N^.P^N nA Y O A ABOUT y—__/ (S)-8-(5-((R)-2-benzylπpipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile

or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound of any one of embodiments 1-42 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

44. A method of inhibiting USP30 in a human, comprising administering a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 43.

45. A method of treating a disease, disorder, or condition associated with USP30, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 43.

46. A method of treating a neurodegenerative or neurological disease, disorder or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 43.

- 31 042925

47. A method of treating a disease, disorder, or condition associated with mitochondrial dysfunction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-42 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 43.

48. The method of any one of embodiments 45-47, wherein the disease, disorder or condition is Parkinson's disease.

The invention is further illustrated by examples and synthesis schemes, but the specific procedures described in the invention should not be construed as limiting the scope and spirit of this invention. It should be understood that the examples are provided only to illustrate specific embodiments and are not intended to limit the scope of the invention. Moreover, it should be understood that there may be various other embodiments, modifications, and equivalents thereof that may be suggested by those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

Examples

Abbreviated symbols.

AMphos-Pd G3 [4-(ditert-butylphosphino)-X,X-dimethylaniline-2-(2'aminobiphenyl)]palladium(P) methanesulfonate BGG bovine γ-globulin Vos Tert-butyloxycarbonyl CbzCl benzyl chloroformate δ Chemical shift DCM dichloromethane DIEA N,N-diisopropylethylamine DIPEA N,N-diisopropylethylamine DMF Ν,N - dimethyl formamide DMSO dimethyl sulfoxide NHMR proton nuclear magnetic resonance HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3tetramethylisouronium hexafluorophosphate HPLC high performance liquid chromatography Hz hertz LCMS liquid chromatography-mass spectrometry NMP N-methyl-2-pyrrolide he r.t. room temperature RT retention time T.F.A. Trifluoroacetic acid XPhos-Pd 3G (2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,G-biphenyl)[2- (2'-amino-1, G-biphenyl)]-palladium(P) methanesulfonate

Example A: Description of the Ubiquitin-Rhodamine 110 Biochemical Assay to Determine USP30 Activity.

The assay was performed in a final volume of 6 μl in assay buffer containing 20 mM Tris-HCl (pH 8.0, (1 M Tris-HCl solution pH 8.0; Corning 46-031-CM)), 1 mM GSH (L- reduced glutathione, SigmaAldrich, G4251-100G), 0.03% BGG (0.22 µM, filtered, Sigma, G7516-25G) and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point 3-fold serial dilutions in DMSO were predispensed into 1536 assay plates (Corning, #3724BC) to create a final test concentration of 25 μM to 1.3 nM, the maximum and minimum dose, respectively. The concentration and duration of incubation were optimized to achieve the maximum signal-to-background ratio while maintaining initial rate conditions at a fixed substrate concentration (<<Km). The final concentration of enzyme (recombinant human USP30, Boston Biochem, catalog no. E-582) in the assay was 0.4 nM. The final substrate concentration (Ub-Rh110; Ubiquitin-Rhodamine 110, UbiQ-126) was 25 nM. The assay plates were added with 3 μl of 2x enzyme (pre-labeled with compound), pre-incubated for 30 min and then treated with 3 μl of 2x substrate. The fluorescence values of the plate wells were read using an Envision (Perkin Elmer) or PheraSTAR (BMG) plate reader (excitation at 485 nm and emission at 535 nm) 5 times over 11 min, and the slope of the plot obtained from this kinetics reading was used to normalize primary data.

For all assay formats, data were presented as percent inhibition compared to control wells based on the following equation: % inhibition=1-((FLUAveLow)/(AveHigh-AveLow)), where FLU=measured fluorescence, AveLow=average fluorescence in absence enzyme control (n=32), and AveHigh=average fluorescence with DMSO control (n=32). _IC50 values were determined by curve fitting using a standard four-parameter

- 32 042925 of the logistic approximation algorithm included in the Activity Base software package: IDBS XE Designer Model205. Data are selected using the Levenberg-Marquardt algorithm.

When performing a USP30 biochemical assay, compounds were identified having an IC ₅₀ value <10 μM (In some embodiments, compounds were identified having an IC ₅₀ value <5 μM, and in some embodiments, compounds were identified having an IC ₅₀ value < 1 μM. using the analysis in example A).

Data on the activity of the compounds of the present invention in the USP30 biochemical assay in the form of IC ₅₀ values (range of IC ₅₀ values) are presented in table. And below as follows:

-: inactive, +: > 10 µM and < 25 µM, ++: > 1 µM and < 10 µM, +++: > 0.1 µM and < 1 µM, ++++: < 0.1 µM.

Table A

Number connections Structure Chemical name USP30 1С ₅₀ 1-1S \uZh) (8)-8-(5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile +++ 1-1R (R)-8-(5-cyclohexyl-thiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 1-2S Cl L 14-%- V *(8)-8-(5-(tert-butyl)-4chlorothiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++++ 1-2R C.I. Ο Ν Ύ / Ν- Η У JI _/ *(K)-8-(5-(tert-butyl)-4chlorothiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++++ 1-3S (8)-8-(4-chloro-5cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++++ 1-3R (R)-8-(4-chloro-5cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++++ 1-4R DG'uN n (R)-8-(5-(3-cyanoφenyl)pyrimidin-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++

- 33 042925

1-4S ri NJ A^A (8)-8-(5-(3-cyanophenyl)pyrimidin-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-5R a % I N aO (R)-8-(5-(3-chlorophenyl)pyrimidin-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-5S n A Λ A^'' ^C| ΑΑ Al A ⁿ A (8)-8-(5-(3-chlorophenyl)pyrimidin-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-6R ^X N (R)-8-(5-(3-cyanophenyl)-τthiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 1-6S ., O λ— _λ \4 ^n/J! ^Q AJ\N (8)-8-(5-(3-cyanophenyl)-thiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 1-7R A A ΤΒΠ n Ά ^s A/ An A bi (R)-8-(5-(3-chlorophenyl)-thiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 1-7S A A BA ν'ΑΆ s А/ An A ci (8)-8-(5-(3-chlorophenyl)-thiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 1-11R ⁰ j—ί (R)-8-(5-(3-chlorophenyl)isoxazol-3-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile -

- 34 042925

1-11S (8)-8-(5-(3-chlorophenyl)isoxazol-3-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile - 1- 12S,R h i ioyy (4aS,8aR)-7-(5cyclohexylthiazol-2-yl)-8oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile ++ 1-12S,S ChuU ³ (4aS,8aS)-7-(5cyclohexylthiazol-2-yl)-8oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile ++ 1- 12R,R (4aR,8aR)-7-(5cyclohexylthiazol-2-yl)-8oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile +++ 1-14S M ° ^N 4 /=\ II Ji У---/ \ N'^ ⁴ p'N^SV# *(8)-9-oxo-8-(5-phenylthiazol-2yl)-octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile +++ 1-14R v//>O k^-N^ *(R)-9-oκco-8-(5-phenylthiazol-2yl)-octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile ++++ 3-1S nA st^^ (8)-8-(5-cyclohexyl-thiazol-2yl)-4-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile +++ 3-1R oL O-<G...... (R)-8-(5-cyclohexyl-thiazol-2yl)-4-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ ^X C0^ ^L (R)-8-(5-(τpeτ-bytyl)-thiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++

- 35 042925

4-lS,R ^X N ^X Y \__J H (4aS,8aR)-7-(5cyclohexylthiazol-2-yl)octahydro-2,7-naphthyridine2(1H)-carbonitrile ++ 4-lR,S η UYA 1 1 (4aR,8aS)-7-(5cyclohexylthiazol-2-yl)octahydro-2,7-naphthyridine2(1H)-carbonitrile ++ 5-lR,R 'H-o ^;E (3aR,7aR)-2-(5cyclohexylthiazol-2-yl)-3 oxooctahydro-5H-pyrrolo[3,4c]pyridin-5-carbonitrile + 5-lS,S (3aS,7aS)-2-(5cyclohexylthiazol-2-yl)-3 oxooctahydro-5H-pyrrolo[3,4c]pyridin-5-carbonitrile ++ 5-2R,R _ _x SKHNHE (3 aR,7aR)-2-(5 -(3-cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile - 5-2S,S (Za8,7a8)-2-(5-(3-cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile + 6-1R O οό if U /)\ About N-U\ Cl (R)-8-(5-(τpeτ-bytyl)-4chlorothiazol-2-yl)-6,9dioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++ 6-1S O xL ^ ^N ^c-kx ^N -^S ₄ / P T /G~\ Ο NX ^X Cl (8)-8-(5-(tert-butyl)-4chlorothiazol-2-yl)-6,9dioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile ++++

- 36 042925

1-113S *(S)-9-okco-8-(5-(2- phenoxyphenyl)thiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile ++++ 1-113R si *(R)-9-okco-8-(5-(2- phenoxyphenyl)thiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile ++++ 1-114R Ο XqAaR) (R)-9-okco-8-(5-(2phenoxyphenyl)-1H-pyrazol-3 yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile +++ 1-114S C XqAjRd (S)-9-okco-8-(5-(2phenoxyphenyl)-1H-pyrazol-3 yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile +++ 1-115R (R)-8-(5-(3 -(azetidin-1ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-115S X.0..AZQ (S)-8-(5-(3 -(azetidin-1ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-116R ζ¥'6-ο X C.I. (R)-8-(5-(τpeτ-bytyl)-4chlorothiazol-2-yl)-9a-fluoro-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++

- 37 042925

1-116S / ¹ ϊ I / \ o N-_// \ Cl (8)-8-(5-(tert-butyl)-4chlorothiazol-2-yl)-9a-fluoro-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++ 1-117R (R)-8-(5-cyclohexylthiazol-2yl)-9a-methyl-9-oxooctahydro2H-pyrazino[1,2-a]-pyrazin-2carbonitrile ++++ 1-117S iA A UU ^s V _ / (S)-8-(5-cyclohexylthiazol-2yl)-9a-methyl-9-oxooctahydro2H-pyrazino[1,2-a]-pyrazin-2carbonitrile ++ 1118R,S О S Ί—\ |\Y li YY ^N \ / o να ⁴ — ¹ (A)-8-(5-((8)-2-benzylpiperidin1 -yl)-thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile ++++ 1- 118R,R o _ζ / ^Ν ·^ν ^Ν \/ ^δ / \ 1Y П UY ^N \ J ο nA ⁴ — ^J (R)-8-(5-((R)-2benzylpiperidin-1 -yl)-thiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile +++ 1- 118S,S P 1 ^N 1 ' YY /У-NJ o nA ⁴ - ¹ (8)-8-(5-((8)-2-benzylpiperidin1 -yl)-thiazol-2-yl)-9- oxooctahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile +++ 1118S,R O X ^N X \ UvXup / \ YYY ) 0 NA ' (8)-8-(5-((K)-2-benzylpiperidine- 1 -yl)-thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile +++

Synthesis of the compound.

Intermediate B'-1. Synthesis of tert-butyl-8-oxooctahydro-2,7-naphthyridine-2(1H)carboxylate.

A protected heterocyclic carbamate (such as a Boc-protected piperidine carbamate derivative) is reduced to a ring double bond with a metal hydride, then a base such as triethylamine and methanesulfonyl chloride are added. The ring double bond is then functionalized using a regioselective reagent such as trimethylsilylacetonitrile with a metal reagent such as n-butyllithium followed by desilylation in the presence of CsF. The nitrile group is reduced to an amine, for example, by hydrogenation in the presence of palladium on carbon and Raney nickel. The ring was capped with ammonia and methanol in acetonitrile to give Boc-protected oxo-octahydro-2,7-naphthyridine (intermediate B'-1) as a mixture of diastereoisomers.

- 38 042925

Intermediate B'-2. Synthesis of tert-butyl-9-oxo-hexahydro-1H-pyrazino[1,2-a]pyrazine2(6H)-carboxylate.

Step 1. 1-tert-Butyl-3-methyl-4-(2-(tert-butoxycarbonylamino)ethyl)piperazine-1,3-dicarboxylate.

A solution of tert-butyl(2-oxoethyl)carbamate (4.89 g, 30.7 mmol) in 1,2-dichloroethane (50 ml) was added to a solution of 1-(tert-butyl)-3-methylpiperazine-1,3- dicarboxylate (5 g, 20.5 mmol) in 1,2-dichloroethane (25 ml). The solution was stirred at 25 °C in a nitrogen atmosphere for 30 min. Sodium triacetoxyborohydride (8.69 g, 41.0 mmol) was added and the resulting mixture was stirred at 25°C for 15 hours. The reaction was stopped by adding water (50 ml) at 25°C. The resulting mixture was extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and the solids were filtered. The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica gel (eluting with 1:1 ethyl acetate/petroleum ether) to give 1-tert-butyl-3-methyl-4-(2-(tert-butoxycarbonylamino)ethyl)piperazine-1,3-dicarboxylate as yellow oils (5.1 g, 64%). LCMS (ES, m/z): 388 [M+H]+.

Step 2. Methyl 1-(2-aminoethyl)piperazine-2-carboxylate 2,2,2-trifluoroacetate.

Trifluoroacetic acid (10 ml) was added dropwise to a cooled to 0°C solution of 1-tert-butyl-3-methyl-4-(2-(tert-butoxycarbonylamino)ethyl)piperazine-1,3-dicarboxylate (5.1 g, 13 .1 mmol) in dichloromethane (30 ml). The reaction solution was stirred at 25°C for 6 hours. The reaction mixture was concentrated in vacuo to obtain methyl 1-(2-aminoethyl)piperazine-2-carboxylate-2,2,2-trifluoroacetate (4.5 g). LCMS (ES, m/z): 188 [M+H] ⁺ .

Step 3. Hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one.

Ammonia in methanol (7 N, 20 ml) was added to a solution of methyl 1-(2-aminoethyl)piperazine-2-carboxylate 2,2,2-trifluoroacetate (4.5 g) in acetonitrile (20 ml), and the solution was stirred at 25 °C for 1 hour. The resulting reaction mixture was concentrated in vacuo to give hexahydro2H-pyrazino[1,2-a]pyrazin-1(6H)-one (3.7 g). LCMS (ES, m/z): 156 [M+H] ⁺ .

Step 4. tert-Butyl-9-oxo-hexahydro-1 H-pyrazino [1,2-a]pyrazine-2(6H)-carboxylate.

Ditert-butyl dicarbonate (6.25 g, 28.7 mmol) was added to a mixture of hexahydro-2H-pyrazino[1,2a]pyrazin-1(6H)-one (3.7 g, 23.9 mmol) and saturated aqueous solution sodium carbonate (40 ml) in dioxane (60 ml). The reaction mixture was stirred at 25 °C for 14 h. The resulting mixture was diluted with water (30 ml), and the resulting mixture was extracted with dichloromethane (3x60 ml). The combined organic layers were washed with brine (3x30 ml), dried over anhydrous sodium sulfate, and the solids were filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:15 methanol/dichloromethane) to give tert-butyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-carboxylate as a yellow solid (1 .9 g, 30%). 'H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.78 (br.s, 1H), 4.28-4.22 (m, 1H), 3.87-3, 81 (m, 1H), 3.28-3.24 (m, 1H), 3.08-3.06 (m, 1H), 2.87-2.80 (m, 3H), 2.60- 2.56 (m, 1H), 2.44-2.33 (m, 2H), 2.11-2.07 (m, 1H), 1.41 (s, 9H). LCMS (ESI, m/z): 256 [M+H] ⁺ .

Example 1-1. Synthesis of (S)-8-(5-cyclohexylthiazol-2-yl)-9-oxohexahydro-1H-pyrazino[1,2a]pyrazin-2(6H)-carbonitrile and (R)-8-(5-cyclohexylthiazol-2 -yl)-9-oxo-hexahydro-1H-pyrazino-[1,2a]pyrazin-2(6H)-carbonitrile.

Step 1. 2-Bromo-5-cyclohexyl-1,3-thiazole.

A mixture of 5-cyclohexyl-1,3-thiazol-2-amine (600 mg, 3.29 mmol), tert-butylnitrile (0.390 ml, 3.83 mmol) and copper(II) bromide (1.47 g, 6. 58 mmol) in acetonitrile (4 ml) was stirred for 3 hours at

- 39 042925 room temperature. The reaction was stopped by adding water (6 ml). The resulting mixture was extracted with ethyl acetate (3x15 ml). The combined organic layers were washed with brine (15 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10/1 petroleum ether/ethyl acetate) to give 2-bromo-5-cyclohexyl-1,3-thiazole (200 mg, 22%) as a light yellow oil. LCMS (ES, m/z): 246, 248 [M+H]+.

Step 2. tert-Butyl-8-(5-cyclohexyl-1,3-thiazol-2-yl)-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazine-2-carboxylate.

A mixture of 2-bromo-5-cyclohexyl-1,3-thiazole (200 mg, 0.816 mmol), tert-butyl-9-oxooctahydro-1H[1,4]diazino[1,2-a]pyrazine-2-carboxylate ( B'-2, 250 mg, 0.979 mmol), cesium carbonate (532 mg, 1.63 mmol) and methanesulfonato adduct (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)( 2'amino-1,1'-biphenyl-2-yl)palladium(P) with dichloromethane (68.7 mg, 0.082 mmol) in dioxane (6 ml) was stirred for 36 hours at 120°C and then cooled to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with 1/1 petroleum ether/ethyl acetate) to give tert-butyl-8-(5-cyclohexyl-1,3-thiazol-2-yl)-9oxooctahydro-1H-[1,4] diazino[1,2-a]pyrazine-2-carboxylate (70.0 mg, 20%) as a yellow solid. LCMS (ES, m/z): 421 [M+H] ⁺ .

tert-Butyl-9-oxooctahydro-1H-[1,4]diazino[1,2-a]pyrazine-2-carboxylate can be purchased from manufacturers or can be synthesized, for example, in accordance with the procedure in example 1- 1B' below.

Step 3. 2-(5-Cyclohexyl-1,3-thiazol-2-yl)octahydro-1H-[1,4]diazino[1,2-a]pyrazin-1-one trifluoroacetate.

A solution of tert-butyl-8-(5-cyclohexyl-1,3-thiazol-2-yl)-9-oxooctahydro-1H-[1,4]diazino[1,2-a]pyrazin-2-carboxylate (70, 0 mg, 0.167 mmol) and trifluoroacetic acid (0.8 ml, 10.1 mmol) in dichloromethane (4 ml) were stirred for 2 hours at room temperature. The resulting solution was concentrated under reduced pressure to give 2-(5-cyclohexyl-1,3-thiazol-2-yl)octahydro-1H[1,4]diazino[1,2-a]pyrazin-1-one trifluoroacetate (71, 0 mg, crude) as a light yellow oil. LCMS (ES, m/z): 321 [M+H] ⁺ .

Step 4. 8-(5-Cyclohexyl-1,3-thiazol-2-yl)-9-oxo-octahydro-1H-[1,4]diazino[1,2-a]pyrazin-2carbonitrile.

2-(5-cyclohexyl-1,3-thiazol-2-yl)octahydro-1H-[1,4]diazino[1,2-a]pyrazin-1-one trifluoroacetate mixture (40.0 mg, 0.096 mmol) , sodium bicarbonate (105 mg, 1.25 mmol) and cyanogen bromide (13.2 mg, 0.125 mmol) in N,N-dimethylformamide (2 ml) were stirred for 1 hour at room temperature. The reaction was stopped by adding water/ice at 0°C. The resulting mixture was extracted with ethyl acetate (3x15 ml). The combined organic layers were washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (35.0 mg) was purified by preparative HPLC (column: XBridge Shield RP18 OBD, 5 mm, 19x150 mm; mobile phase A: water (containing 0.05% ammonium bicarbonate), and B: acetonitrile (46% to 60 % for 7 min); flow rate: 20 ml/min; detector: 220/254 nm) to obtain 8-(5-cyclohexyl1,3-thiazol-2-yl)-9-oxooctahydro-1H-[1,4] diazino[1,2-a]pyrazine-2-carbonitrile (12.0 mg, 4%) as a white solid. LCMS (ES, m/z): 346 [M+H] ⁺ .

Step 5. (S)-8-(5-Cyclohexylthiazol-2-yl)-9-oxo-hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)carbonitrile and (R)-8-( 5-cyclohexylthiazol-2-yl)-9-oxo-hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)carbonitrile.

8-(5-Cyclohexyl-1,3-thiazol-2-yl)-9-oxooctahydro-1H-[1,4]diazino[1,2-a]pyrazine-2-carbonitrile (12.0 mg, 0.034 mmol ) were separated by chiral HPLC (column: Chiralpak IA, 2 x 25 cm, 5 mm; mobile phase A: methanol (containing 0.1% diethylamine), and B: dichloromethane (70% hold for 20 min); flow rate: 18 ml/min; detector: 220/254 nm; RT1: 7.121 min and RT2: 12.341 min) obtaining:

(S)-8-(5-cyclohexylthiazol-2-yl)-9-oxo-hexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-carbonitrile (RT1: 7.121 min) (3.60 mg, 30%) as a white solid. 1H-NMR (DMSO- _d6 , 400 MHz) δ (ppm) 7.29 (s, 1H), 4.22-4.19 (m, 1H), 3.84-3.80 (m , 1H), 3.78-3.73 (m, 1H), 3.40-3.32 (m, 1H), 3.18-3.10 (m, 4H), 2.95-2.92 (m, 1H), 2.84-2.71 (m, 2H), 2.43-2.38 (m, 1H), 1.98-1.92 (m, 2H), 1.78-1 .74 (m, 2H), 1.69-1.66 (m, 1H), 1.43-1.34 (m, 4H), 1.27-1.98 (m, 1H). Absolute stereochemistry is assigned arbitrarily; and (R)-8-(5-cyclohexylthiazol-2-yl)-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazin-2(6H)-carbonitrile (RT2: 12.341 min) (3.10 mg , 26%) as a white solid. LCMS (ES, m/z):346 [M+H] ⁺ . 1H-NMR (DMSO-d6, 400 MHz) δ (ppm) 7.29 (s, 1H), 4.22-4.19 (m, 1H), 3.84-3.80 (m, 1H), 3.78-3.73(m, 1H), 3.40-3.32(m, 1H), 3.18-3.10(m, 4H), 2.95-2.92( m, 1H), 2.83-2.68 (m, 2H), 2.43-2.38 (m, 1H), 1.98-1.91 (m, 1H), 1.81-1. 76 (m, 2H), 1.72-1.67 (m, 1H), 1.45-1.28 (m, 4H), 1.27-1.97 (m, 1H). Absolute stereochemistry is assigned arbitrarily.

- 40 042925

Example 1-12. Synthesis of (4aS,8aS)-7-(5-cyclohexylthiazol-2-yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile.

Boc-protected oxo-octahydro-2,7-naphthyridine (B'-1) was cross-coupled with 2bromo-5-cyclohexylthiazole using a metal catalyst (eg XPhos-Pd 3G). Next, the Boc protecting group was removed in the presence of trifluoroacetic acid and replaced with a nitrile group in the presence of BrCN and a base (eg NaHCO ₃ ).

Example 2-1. Synthesis of (R)-8-(5-cyclohexylthiazol-2-yl)-4,9-dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

(R)-2-(((Benzyloxy)carbonyl)amino)-3-((tert-butoxy-carbonyl)amino)propanoic acid can be coupled with 5-cyclohexylthiazol-2-amine using a standard coupling reagent ( ie HATU) and base (ie DIEA) in a suitable solvent, and the Boc group can then be removed using either TFA or HCl in a suitable solvent. The resulting amine can be reacted with methyl 2-bromoacetate, resulting in cyclization into a piperazinone ring while removing the Cbz group by hydrogenation. Piperazinone can be protected with a Boc group, and bis-alkylation with an appropriate electrophile (ie ethane-1,2-diylbis(trifluoromethanesulfonate)) allows the formation of a bicyclic ring structure. Then, the Boc protecting group can be removed and replaced with a nitrile group.

Example 3-1. Synthesis of (S)-8-(5-cyclohexylthiazol-2-yl)-4-oxooctahydro-2H-nyrazino[1,2-a]pyrazin2-carbonitrile.

tert-Butyl-(R)-(piperazin-2-ylmethyl)carbamate was protected with a Cbz group in the presence

CbzCl. Then a bicycle was formed in the presence of 2-chloroacetyl chloride, then NaH was added. The Cbz group was removed in the presence of _H2 and Pd/C, followed by a Buchwald coupling reaction with 2-bromo-5cyclohexylthiazole. Next, the Boc protecting group was removed in the presence of trifluoroacetic acid, and the resulting amine was functionalized with a nitrile group in the presence of NaHCO ₃ and BrCN.

Example 4-1. Synthesis of (4aS,8aR)-7-(5-cyclohexylthiazol-2-yl)octahydro-2,7-naphthyridin-2(1H)carbonitrile and (4aR,8aS)-7-(5-cyclohexylthiazol-2-yl)octahydro -2,7-naphthyridine-2(1H)-carbonitrile.

jTVY ) H ₂ ,Pd(OH) ₂ .

Ν NH _______________.” N N S \--/ ----------HN γ N S \/

E Reaction of combination of HOAc\„

I Racemate

BukhvaldaN

I BrCN, | _NaHCO3

Enantiomerically pure Separation of enantiomer products

1,2,3,4-Tetrahydro-2,7-naphthyridine was subjected to a Buchwald coupling reaction with 2-bromo-5cyclohexylthiazole. The resulting compound was then reduced in the presence of H ₂ and Pd(OH) ₂ . The resulting amine was then functionalized with a nitrile group in the presence of NaHCO ₃ and

BrCN to obtain a racemic mixture, which was separated to obtain enantiomerically pure products.

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Example 5-1. Synthesis of (3aR,7aR)-2-(5-cyclohexylthiazol-2-yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

(3aR _, 7aR)-Octahydro-3H-pyrrolo[3,4-c]pyridin-3-one was protected with a Boc group in the presence of (Boc) _2O and _Na2CO3 . The Boc-protected product was cross-coupled with 2-bromo-5cyclohexylthiazole in the presence of a copper catalyst and K ₃ PO ₄ . Next, the protecting group was removed in the presence of trifluoroacetic acid, and the resulting amine was functionalized with a nitrile group in the presence of NaHCO ₃ and BrCN.

Example 5-2. Synthesis of (3a,7a)-2-(5-(3-cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

NC ON

the second eluting isomer tert-Butyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate was subjected to a substitution reaction with 5bromo-2-chloropyrimidine in the presence of DIPEA. The resulting product was subjected to a cross-coupling reaction with (3-cyanophenyl)boronic acid in the presence of AMphos-Pd G3 and K ₃ PO ₄ . Next, the Boc group was removed in the presence of trifluoroacetic acid and the resulting amine was functionalized with a nitrile group in the presence of NaHCO ₃ and BrCN to give (3a,7a)-2-(5-(3cyanophenyl)pyrimidin-2-yl)octahydro-5H- pyrrolo[3,4-c]pyridine-5-carbonitrile as a racemic mixture. Enantiomers were separated by chiral separation.

Example 1-119. Synthesis of 2-(5-cyclohexylthiazol-2-yl)octahydro-5H-pyrrolo[3,4-c]pyridine-5carbonitrile.

tert-Butyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate can be cross-coupled with 2-bromo-5-cyclohexylthiazole. Then, the Boc group can be removed in the presence of trifluoroacetic acid, and the resulting amine can be functionalized with a nitrile group in the presence of NaHCO ₃ and BrCN.

The following compounds were prepared in accordance with the methods described in the invention.

1-2S connection. (S)-8-(5-(tert-Butyl)-4-chlorothiazol-2-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-06, 400 MHz) δ (ppm): 4.14-4.10 (m, 1H), 3.80-3.75 (m, 1H), 3.71- 3.68 (m, 1H), 3.403.37 (m, 1H), 3.28-3.10 (m, 4H), 2.95-2.92 (m, 1H), 2.79-2. 73 (m, 1H), 2.47-2.41 (m, 1H), 1.43 (s, 9H). LCMS (ES, m/z): 354.356 [M+H]+.

Connection 1-2R. (9aR)-8-(5-tert-Butyl-4-chloro-1,3-thiazol-2-yl)-9-oxooctahydro-1H-[1,4]diazino[1,2-a]pyrazin-2 -carbonitrile.

^1H -NMR (DMSO- _d6 , 400 MHz) δ (ppm): 4.14-4.10 (m, 1H), 3.81-3.75 (m, 1H), 3.71 -3.68 (m, 1H), 3.403.37 (m, 1H), 3.28-3.10 (m, 4H), 2.95-2.92 (m, 1H), 2.79-2 .75 (m, 1H), 2.46-2.40 (m, 1H), 1.43 (s, 9H). LCMS (ES, m/z): 354.356 [M+H] ⁺ .

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1-3S connection. ^)-8-(4-Chloro-5-cyclohexylthiazol-2-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

1H-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 4.16-4.12 (m, 1H), 3.82-3.79 (m, 1H), 3.72- 3.68 (m, 1H), 3.413.32 (m, 1H), 3.29-3.25 (m, 1H), 3.21-3.11 (m, 3H), 2.95-2. 92 (m, 1H), 2.85-2.75 (m, 2H), 2.44-2.34 (m, 1H), 1.91-1.87 (m, 2H), 1.78- 1.77 (m, 2H), 1.69-1.67 (m, 1H), 1.39-1.24 (m, 5H). LCMS (ES, m/z): 380, 382 [M+H]+.

Connection 1-3R. (R)-8-(4-Chloro-5-cyclohexylthiazol-2-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 4.16-4.12 (m, 1H), 3.80-3.79 (m, 1H), 3.72-3 .68 (m, 1H), 3.413.32 (m, 1H), 3.28-3.25 (m, 1H), 3.21-3.11 (m, 3H), 2.95-2.92 (m, 1H), 2.84-2.75 (m, 2H), 2.50-2.42 (m, 1H), 1.93-1.90 (m, 2H), 1.84-1 .75 (m, 2H), 1.74-1.68 (m, 1H), 1.39-1.22 (m, 5H). LCMS (ES, m/z): 380, 382 [M+H] ⁺ .

Connection 1-4R. (R)-8-(5-(3-Cyanophenyl)pyrimidin-2-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile

XX

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.76 (t, J=8.0 Hz, 1H), 3.96-3.83 (m, 2H), 3, 71-3.64 (m, 1H), 3.42-3.30 (m, 2H), 3.25-3.09 (m, 4H), 2.97-2.94 (m, 1H), 2.82-2.75 (m, 1H), 2.48-2.42 (m, 1H). LCMS (ES, m/z): 360 [M+H] ⁺ .

Connection 1-4S. (S)-8-(5-(3-Cyanophenyl)pyrimidin-2-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

XX a ΧΧ ^ ^ν

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.76 (t, J=8.0 Hz, 1H), 3.96-3.84 (m, 2H), 3, 71-3.64 (m, 1H), 3.42-3.35 (m, 1H), 3.24-3.21 (m, 1H), 3.19-3.17 (m, 3H), 2.97-2.90 (m, 1H), 2.82-2.75 (m, 1H), 2.48-2.42 (m, 1H). LCMS (ES, m/z): 360 [M+H] ⁺ .

Connection 1-5R. (9aR)-8-[5-(3-Chlorophenyl)pyrimidin-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.19 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.56-7.53 (m, 2H), 3.96-3.82 (m, 2H), 3.71-3 .64 (m, 1H), 3.41-3.38 (m, 1H), 3.25-3.11 (m, 4H), 2.962.93 (m, 1H), 2.82-2.75 (m, 1H), 2.48-2.42 (m, 1H). LCMS (ES, m/z): 369 [M+H] ⁺ .

1-5S connection. (9aS)-8-[5-(3-Chlorophenyl)pyrimidin-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 9.19 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.56-7.53 (m, 2H), 3.96-3.82 (m, 2H), 3.68-3 .64 (m, 1H), 3.41-3.38 (m, 1H), 3.25-3.11 (m, 4H), 2.962.93 (m, 1H), 2.82-2.76 (m, 1H), 2.48-2.42 (m, 1H). LCMS (ES, m/z): 371 [M+H] ⁺ .

Connection 1-6R. (9aR)-8-[5-(3-Cyanophenyl)-1,3-thiazol-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2-a]pyrazin-2-carbonitrile .

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.22 (s, 1H), 8.18 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.78 (d, J=7.6

Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 4.31-4.27 (m, 1H), 3.92-3.89 (m, 1H), 3.77 -3.73 (m, 1H), 3.43-3.39 (m, 1H), 3.33-3.30 (m, 1H), 3.23-3.18 (m, 3H), 2 .98-2.95 (m, 1H), 2.84-2.81 (m, 1H), 2.51-2.46 (m, 1H). LCMS (ES, m/z): 365 [M+H] ⁺ .

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Connection 1-6S. (9aS)-8-[5-(3-Cyanophenyl)-1,3-thiazol-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.22 (s, 1H), 8.18 (s, 1H), 7.96 (d, J=8.0 Hz , 1H), 7.78 (d, J=7.6 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 4.31-4.27 (m, 1H), 3 .95-3.86 (m, 1H), 3.77-3.73 (m, 1H), 3.43-3.39 (m, 1H), 3.33-3.31 (m, 1H) , 3.27-3.18 (m, 3H), 2.98-2.95 (m, 1H), 2.85-2.81 (m, 1H), 2.48-2.42 (m, 1H). LCMS (ES, m/z): 365 [M+H] ⁺ .

Connection 1-7R. (9aR)-8-[5-(3-Chlorophenyl)-1,3-thiazol-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.11 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.31-4.27 (m, 1H), 3.89-3.85 (m, 1H), 3.76-3.73 (m, 1H), 3.42-3.39 (m, 1H), 3.33-3.29 (m, 1H ), 3.27-3.17 (m, 3H), 2.98-2.95. LCMS (ES, m/z): 374.376 [M+H] ⁺ .

Connection 1-7S. (9aS)-8-[5-(3-Chlorophenyl)-1,3-thiazol-2-yl]-9-oxooctahydro-1H-[1,4]diazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.11 (s, 1H), 7.78 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 4.28-4.27 (m, 1H), 3.89-3.85 (m, 1H), 3.77-3.73 (m, 1H), 3.42-3.39 (m, 1H), 3.33-3.29 (m, 1H ), 3.27-3.17 (m, 3H), 2.98-2.95 (m, 1H), 2.85-2.80 (m, 1H), 2.51-2.43 (m , 1H). LCMS (ES, m/z): 374.376 [M+H] ⁺ .

Connection 1-11R. (R)-8-(5-(3-Chlorophenyl)isoxazol-3-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.73 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.59-7 .42 (m, 3H), 3.87-3.72 (m, 2H), 3.49-3.39 (m, 2H), 3.19-2.96 (m, 5H), 2. 89-2.82 (m, 1H), 2.56-2.49 (m, 1H) LCMS (ES, m/z): 358, 360 [M+H] ⁺ .

Connection 1-11S. (S)-8-(5-(3-Chlorophenyl)isoxazol-3-yl)-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.73 (s, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.59-7 .36 (m, 3H), 3.87-3.72 (m, 2H), 3.53-3.39 (m, 2H), 3.19-2.96 (m, 5H), 2.89 -2.82 (m, 1H), 2.56-2.49 (m, 1H). LCMS (ES, m/z): 358, 360 [M+H] ⁺ .

Connection 1-12S,R. (4aS,8aR)-7-(5-Cyclohexylthiazol-2-yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.27 (s, 1H), 4.15-4.11 (m, 1H), 4.03-3.96 (m , 1H), 3.93-3.90 (m, 1H), 3.34-3.31 (m, 1H), 3.23-3.19 (m, 1H), 3.13-3.07 (m, 1H), 2.92-2.90 (m, 1H), 2.84-2.79 (m, 1H), 2.22-2.08 (m, 2H), 2.01-1 .92 (m, 3H), 1.82-1.75 (m, 2H), 1.84-1.62 (m, 2H), 1.60-1.47 (m, 1H), 1.46 -1.28 (m, 4H), 1.271.18 (m, 1H). LCMS (ES, m/z): 345 [M+H]+.

Connection 1-12R,R. (4aR,8aR)-7-(5-Cyclohexylthiazol-2-yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile.

1H-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 7.25 (s, 1H), 4.27-4.22 (m, 1H), 3.85-3.72 ( m, 2H), 3.42-3.34 (m, 1H), 3.08-3.00 (m, 2H), 2.82-2.77 (m, 1H), 2.63-2, 57 (m, 1H), 2.04-2.02 (m, 1H), 1.93-1.90 (m, 2H), 1.86-1.67 (m, 6H), 1.48- 1.30 (m, 5H), 1.29-1.18 (m, 1H). LCMS (ES, m/z): 345 [M+H] ⁺ .

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Connection 1-12S,S. (4aS,8aS)-7-(5-Cyclohexyl-thiazol-2-yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile.

'H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.27 (s, 1H), 4.15-4.11 (m, 1H), 4.03-3.96 ( m, 1H), 3.93-3.90 (m, 1H), 3.34-3.31 (m, 1H), 3.23-3.19 (m, 1H), 3.13-3. 07 (m, 1H), 2.92-2.90 (m, 1H), 2.84-2.79 (m, 1H), 2.22-2.08 (m, 2H), 2.01- 1.92 (m, 3H), 1.82-1.75 (m, 2H), 1.84-1.62 (m, 2H), 1.60-1.47 (m, 1H), 1. 46-1.28 (m, 4H), 1.271.18 (m, 1H). LCMS (ES, m/z): 345 [M+H] ⁺ .

Connection 1-14S. *(S)-9-Oxo-8-(5-phenylthiazol-2-yl)octahydro-2H-pyrazino[1,2-a]pyrazine-2carbonitrile.

'H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 7.80 (s, 1H), 7.65 (d, J=7.2 Hz, 2H), 7.44 ( t, J=7.6 Hz, 2H), 7.34 (t, J=7.2 Hz, 1H), 4.31-4.26 (m, 1H), 3.92-3.84 (m , 1H), 3.77-3.73 (m, 1H), 3.43-3.39 (m, 1H), 3.32-3.28 (m, 1H), 3.23-3.15 (m, 3H), 2.97-2.94 (m, 1H), 2.84-2.77 (m, 1H), 2.49-2.44 (m, 1H). LCMS (ES, m/z): 340 [M+H] ⁺ .

Connection 1-14R. *(R)-9-Oxo-8-(5-phenylthiazol-2-yl)octahydro-2H-pyrazino[1,2-a]pyrazine-2carbonitrile.

'H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.80 (s, 1H), 7.65 (d, J=7.2 Hz, 2H), 7.46-7 .42 (m, 2H), 7.34 (t, J=7.2 Hz, 1H), 4.30-4.26 (m, 1H), 3.92-3.84 (m, 1H), 3.77-3.73 (m, 1H), 3.43-3.39 (m, 1H), 3.32-3.28 (m, 1H), 3.23-3.15 (m, 3H ), 2.97-2.94 (m, 1H), 2.84-2.77 (m, 1H), 2.49-2.44 (m, 1H). LCMS (ES, m/z): 340 [M+H] ⁺ .

Connection 1-15S. (S)-8-(5-(tert-Butyl)thiazol-2-yl)-9a-methyl-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

'H-NMR (DMSO-d6, 300 MHz) δ (ppm): 7.28 (s, 1H), 4.15-4.09 (m, 1H), 3.93-3.86 ( m, 1H), 3.34-3.23 (m, 5H), 3.00-2.96 (m, 1H), 2.92-2.83 (m, 1H), 2.73-2. 67 (m, 1H), 1.40 (s, 3H), 1.34 (s, 9H). LCMS (ES, m/z): 334 [M+H] ⁺ .

Connection 1-15R. (R)-8-(5-(tert-Butyl)thiazol-2-yl)-9a-methyl-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

'H-NMR (DMSO- _d6 , 300 MHz) δ (ppm): 7.28 (s, 1H), 4.15-4.09 (m, 1H), 3.93-3.86 (m, 1H), 3.34-3.23 (m, 5H), 2.99-2.96 (m, 1H), 2.92-2.83 (m, 1H), 2.73-2 .67 (m, 1H), 1.40 (s, 3H), 1.34 (s, 9H). LCMS (ES, m/z): 334 [M+H] ⁺ .

Connection 3-1R. (R)-8-(5-Cyclohexylthiazol-2-yl)-4-oxooctahydro-2H-pyrazino[1,2-a]pyrazin2-carbonitrile.

'H-NMR (DMSO- _d6 , 300 MHz) δ (ppm): 6.89 (s, 1H), 4.46-4.43 (m, 1H), 3.98-3.89 (m, 3H), 3.82-3.77 (m, 3H), 2.95-2.80 (m, 3H), 2.72-2.67 (m, 1H), 1.93-1 .89 (m, 2H), 1.74-1.71 (m, 2H), 1.67-1.64 (m, 1H), 1.38-1.14 (m, 6H). LCMS (ES, m/z): 346 [M+H] ⁺ .

3-1S connection. (S)-8-(5-Cyclohexylthiazol-2-yl)-4-oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2carbonitrile.

'H-NMR (DMSO- _d6 , 300 MHz) δ (ppm): 6.89 (s, 1H), 4.46-4.43 (m, 1H), 3.97-3.89 (m, 3H), 3.84-3.77 (m, 3H), 2.95-2.80 (m, 3H), 2.72-2.67 (m, 1H), 1.93-1 .89 (m, 2H), 1.74-1.71 (m, 2H), 1.67-1.64 (m, 1H), 1.40-1.12 (m, 6H). LCMS (ES, m/z): 346 [M+H]+.

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Connection 4-1S,R. (4aS,8aR)-7-(5-Cyclohexylthiazol-2-yl)octahydro-2,7-naphthyridine-2(1H)carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 6.81 (s, 1H), 3.49-3.19 (m, 4H), 3.09-3.07 (m , 1H), 2.68-2.63 (m, 1H), 2.09-2.07 (m, 3H), 1.98-1.90 (m, 4H), 1.84-1.70 (m, 4H), 1.69-1.52 (m, 3H), 1.38-1.12 (m, 5H). LCMS (ES, m/z): 331 [M+H] ⁺ .

Connection 4-1R,S. (4aR,8aS)-7-(5-Cyclohexylthiazol-2-yl)octahydro-2,7-naphthyridine-2(1H)carbonitrile.

1H-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 6.81 (s, 1H), 3.48-3.39 (m, 3H), 3.38-3.19 ( m, 4H), 3.09-3.07 (m, 1H), 2.68-2.63 (m, 1H), 2.08-1.88 (m, 4H), 1.87-1. 72 (m, 4H), 1.70-1.56 (m, 3H), 1.36-1.28 (m, 4H), 1.27-1.17 (m, 1H). LCMS (ES, m/z): 331 [M+H] ⁺ .

Connection 5-1 R,R. (3 aR,7aR)-2-(5-Cyclohexylthiazol-2-yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.22 (s, 1H), 3.95-3.93 (m, 1H), 3.78-3.75 (m , 1H), 3.66-3.62 (m, 1H), 3.40-3.38 (m, 1H), 3.36-3.26 (m, 1H), 3.04-3.01 (m, 2H), 2.85-2.81 (m, 1H), 2.66-2.62 (m, 1H), 1.98-1.85 (m, 3H), 1.83-1 .67 (m, 3H), 1.47-1.31 (m, 5H), 1.30-1.19 (m, 1H). LCMS (ES, m/z): 331 [M+H] ⁺ .

Connection 5-1S,S. (3 aS,7aS)-2-(5-Cyclohexylthiazol-2-yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.22 (s, 1H), 3.95-3.93 (m, 1H), 3.78-3.75 (m , 1H), 3.66-3.62 (m, 1H), 3.40-3.38 (m, 1H), 3.35-3.26 (m, 1H), 3.04-3.01 (m, 2H), 2.85-2.81 (m, 1H), 2.66-2.62 (m, 1H), 1.98-1.85 (m, 3H), 1.83-1 .67 (m, 3H), 1.47-1.31 (m, 5H), 1.30-1.19 (m, 1H). LCMS (ES, m/z): 331 [M+H] ⁺ .

Connection 5-2R,R. (3aR,7aR)-2-(5-(3-Cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.79 (s, 2H), 8.18 (s, 1H), 8.02 (d, J=8.0 Hz, 1H ), 7.78 (d, J=7.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 3.69-3.61 (m, 2H), 3.59 -3.48 (m, 2H), 3.42-3.28 (m, 2H), 3.26-3.21 (m, 1H), 3.15-3.10 (m, 1H), 2 .52-2.50 (m, 1H), 2.46-2.42 (m, 1H), 1.83-1.76 (m, 1H), 1.57-1.54 (m, 1H) . LCMS (ES, m/z): 331 [M+H] ⁺ .

Connection 5-2S,S. (3aS,7aS)-2-(5-(3-Cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.79 (s, 2H), 8.18 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 3.69-3.61 (m, 2H), 3, 59-3.48 (m, 2H), 3.41-3.28 (m, 2H), 3.26-3.21 (m, 1H), 3.15-3.09 (m, 1H), 2.52-2.50 (m, 1H), 2.46-2.41 (m, 1H), 1.83-1.76 (m, 1H), 1.58-1.53 (m, 1H ). LCMS (ES, m/z): 331 [M+H]+.

Connection 6-1R. (R)-8-(5-(tert-Butyl)-4-chlorothiazol-2-yl)-6,9-dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 4.63 (dd, J=11.2, 3.6 Hz, 1H), 4.59-4.49 (m, 2H), 4.45-4.38 (m, 1H), 3.73 (dd, J=12.4, 3.2 Hz, 1H), 3.52-3.49 (m, 1H), 3 .39-3.34 (m, 1H), 3.13-3.09 (m, 1H), 2.92-2.87 (m, 1H), 1.43 (s, 9H). LCMS (ES, m/z): 368, 370 [M+H] ⁺ .

- 46 042925

Connection 6-1S. (S)-8-(5-(tert-Butyl)-4-chlorothiazol-2-yl)-6,9-dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 4.63 (dd, J=11.2, 3.6 Hz, 1H), 4.59-4.49 (m, 2H ), 4.45-4.38 (m, 1H), 3.73 (dd, J=12.4, 3.2 Hz, 1H), 3.52-3.49 (m, 1H), 3, 39-3.34 (m, 1H), 3.13-3.09 (m, 1H), 2.92-2.87 (m, 1H), 1.43 (s, 9H). LCMS (ES, m/z): 368, 370 [M+H] ⁺ .

Connection 1-113S. *(S)-9-Oxo-8-(5-(2-phenoxyphenyl)thiazol-2-yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 8.09 (s, 1H), 7.91 (d, J=6.8 Hz, 1H), 7.42- 7.33 (m, 3H), 7.26 (t, J=7.2 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.01-6.99 (m , 3H), 4.28-4.24 (m, 1H), 3.88-3.81 (m, 1H), 3.73-3.70 (m, 1H), 3.42-3.36 (m, 1H), 3.25-3.10 (m, 4H), 2.95-2.92 (m, 1H), 2.80-2.76. LCMS (ES, m/z): 432 [M+H] ⁺ .

Connection 1-113R. *(K)-9-Oxo-8-(5-(2-phenoxy-phenyl)thiazol-2-yl)octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.10 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 7.42-7, 34 (m, 3H), 7.26 (t, J=7.2 Hz, 1H), 7.15 (t, J=7.2 Hz, 1H), 7.01-6.99 (m, 3H), 4.28-4.24 (m, 1H), 3.88-3.81 (m, 1H), 3.73-3.70 (m, 1H), 3.50-3.48 (m, 1H ), 3.35-3.10 (m, 4H), 2.95-2.92 (m, 1H), 2.80-2.76 (m, 1H), 2.48-2.38 (m , 1H). LCMS (ES, m/z): 432 [M+H] ⁺ .

Connection 1-114S. (8)-9-Oxo-8-(5-(2-phenoxyphenyl)-1H-pyrazol-3-yl)octahydro-2H-pyrazino[1,2-a]pyrazine-2-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 12.97 (br.s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.41- 7.36 (m, 3H), 7.27 (t, J=7.2 Hz, 1H), 7.16-7.10 (m, 2H), 7.01-6.96 (m, 3H), 3 ,3.96-3.93 (m, 1H), 3.77-3.66 (m, 2H), 3.20-3.19 (m, 1H), 3.17-3.01 (m, 3H), 2.92-2.89 (m, 1H), 2.70-2.67 (m, 1H), 2.39-2.33 (m, 2H). LCMS (ES, m/z): 415 [M+H] ⁺ .

Connection 1-114R. (C)-9-Oxo-8-(5-(2-phenoxyphenyl)-1H-pyrazol-3-yl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile.

1H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 12.97 (br.s, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.41 -7.36 (m, 3H), 7.27 (t, J=7.2 Hz, 1H), 7.16-7.11 (m, 2H), 7.01-6.96 (m, 3H), 3.96-3.92 (m, 1H), 3.76-3.66 (m, 2H),3.38-3.34 (m, 1H), 3.20-3.19 (m, 1H ), 3.17-3.03 (m, 3H), 2.92-2.89 (m, 1H), 2.70-2.67 (m, 1H) 2.38-2.33 (m, 1H). LCMS (ES, m/z): 415 [M+H] ⁺ .

Connection 1-115R. (R)-8-(5-(3-(Azetidin-1-ylmethyl)phenyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile.

1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.97 (s, 1H), 7.52-7.50 (m, 2H), 7.36 (t, J=8 .0 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.30-4.26 (m, 1H), 3.90-3.85 (m, 1H), 3 .76-3.73 (m, 1H), 3.55 (s.2H), 3.28-3.21 (m, 2H), 3.173.13 (m, 7H), 2.97-2.94 (m, 1H), 2.84-2.78 (m, 1H), 2.51-2.41 (m, 1H), 2.02-1.98 (m, 2H). LCMS (ES, m/z): 409 [M+H]+.

- 47 042925

Connection 1-115S. (S)-8-(5-(3-(Azetidin-1-ylmethyl)phenyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile.

¹ H-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.98 (s, 1H), 7.52-7.51 (m, 2H), 7.36 (t, J= 7.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 4.30-4.27 (m, 1H), 3.90-3.85 (m, 1H), 3.76-3.73 (m, 1H), 3.56 (s, 2H), 3.31-3.21 (m, 2H), 3.173.13 (m, 7H), 2.97-2. 94 (m, 1H), 2.84-2.78 (m, 1H), 2.51-2.43 (m, 1H), 2.02-1.98 (m, 2H). LCMS (ES, m/z): 409 [M+H]+.

Connection 1-116R. (R)-8-(5-(tert-Butyl)-4-chlorothiazol-2-yl)-9a-fluoro-9-oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 3.50-3.40 (m, 1H), 3.38-3.31 (m, 2H), 3.28-3 .15 (m, 4H), 3.053.01 (m, 1H), 2.82-2.80 (m, 1H), 2.67-2.65 (m, 1H), 1.32 (s, 9H ). LCMS (ES, m/z): 372, 374 [M+H] ⁺ .

Connection 1-116S. (S)-8-(5-(tert-Butyl)-4-chlorothiazol-2-yl)-9a-fluoro-9-oxooctahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 3.48-3.44 (m, 1H), 3.34-3.26 (m, 2H), 3.25- 3.12 (m, 3H), 3.053.02 (m, 1H), 2.84-2.81 (m, 1H), 2.73-2.70 (m, 1H), 2.57-2. 51 (m, 1H), 1.32 (s, 9H). LCMS (ES, m/z): 372, 374 [M+H] ⁺ .

Connection 1-117R. (R)-8-(5-Cyclohexylthiazol-2-yl)-9a-methyl-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.29 (s, 1H), 4.13-4.11 (m, 1H), 3.94-3.88 (m , 1H), 3.39-3.34 (m, 1H), 3.30-3.18 (m, 4H), 3.01-2.96 (m, 1H), 2.89-2.71 (m, 2H), 2.72-2.70 (m, 1H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H), 1.72-1 .69 (m, 1H), 1.42-1.35 (m, 7H), 1.25-1.18 (m, 1H). LCMS (ES, m/z): 360 [M+H] ⁺ .

Connection 1-117S. (S)-8-(5-Cyclohexylthiazol-2-yl)-9a-methyl-9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 7.29 (s, 1H), 4.13-4.09 (m, 1H), 3.94-3.88 ( m, 1H), 3.39-3.32 (m, 1H), 3.30-3.16 (m, 4H), 3.01-2.96 (m, 1H), 2.89-2. 71 (m, 2H), 2.70-2.68 (m, 1H), 1.96-1.94 (m, 2H), 1.76-1.74 (m, 2H), 1.69- 1.66 (m, 1H), 1.42-1.35 (m, 7H), 1.26-1.21 (m, 1H). LCMS (ES, m/z): 360 [M+H] ⁺ .

Connection 1-118R,S. (R)-8-(5-((S)-2-Benzylpiperidin-1-yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO-d6, 400 MHz) δ (ppm): 7.30-7.28 (m, 2H), 7.19-7.18 (m, 3H), 6.79 (s , 1H), 4.22-4.17 (m, 1H), 3.75-3.68 (m, 2H), 3.46-3.44 (m, 1H), 3.41-3.35 (m, 1H), 3.22-3.06 (m, 6H), 2.94-2.91 (m, 1H), 2.87-2.70 (m, 3H), 2.42-2 .38 (m, 1H), 1.80-1.66 (m, 2H), 1.64-1.43 (m, 3H), 1.42-1.38 (m, 1H). LCMS (ES, m/z): 437 [M+H] ⁺ .

Connection 1-118R,R. (R)-8-(5-((R)-2-Benzylpiperidin-1-yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile.

Ή-NMR (DMSO- _d6 , 400 MHz) δ (ppm): 7.30-7.28 (m, 2H), 7.19-7.17 (m, 3H), 6.79 ( s, sch), 4.14-4.12 (m,

-

Claims (48)

1H), 3.81-3.70 (m, 2H), 3.45-3.42 (m, 1H), 3.40-3.35 (m, 1H), 3.22-3.06 ( m, 6H), 2.94-2.91 (m, 1H), 2.87-2.70 (m, 3H), 2.42-2.38 (m, 1H), 1.78-1. 66 (m, 2H), 1.64-1.43 (m, 3H), 1.42-1.38 (m, 1H). LCMS (ES, m/z): 437 [M+H]+. Connection 1-118S,S. (S)-8-(5-((S)-2-Benzylpiperidin-1-yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile. 1H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm): 7.32-7.28 (m, 2H), 7.21-7.17 (m, 3H), 6.79 ( s, 1H), 4.14-4.12 (m, 1H), 3.80-3.69 (m, 2H), 3.43-3.40 (m, 1H), 3.39-3, 35 (m, 1H), 3.23-3.04 (m, 6H), 2.94-2.91 (m, 1H), 2.88-2.70 (m, 3H), 2.42- 2.38 (m, 1H), 1.78-1.66 (m, 2H), 1.64-1.43 (m, 3H), 1.42-1.38 (m, 1H). LCMS (ES, m/z): 437 [M+H] ⁺ . Connection 1-118S,R. (S)-8-(5-((R)-2-Benzylpiperidin-1-yl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2-carbonitrile. ^1H -NMR (DMSO- _d6 , 400 MHz) δ (ppm): 7.32-7.28 (m, 2H), 7.21-7.17 (m, 3H), 6.79 (s, 1H), 4.14-4.12 (m, 1H), 3.80-3.69 (m, 2H), 3.43-3.40 (m, 1H), 3.39-3 .35 (m, 1H), 3.23-3.04 (m, 6H), 2.94-2.91 (m, 1H), 2.88-2.70 (m, 3H), 2.42 -2.38 (m, 1H), 1.78-1.66 (m, 2H), 1.64-1.43 (m, 3H), 1.42-1.38 (m, 1H). LCMS (ES, m/z): 437 [M+H] ⁺ . Equivalents. The above written description of the invention is considered sufficient to enable one skilled in the art to practice the embodiments of the invention. The above description and examples detail specific embodiments and the embodiment considered best by the inventors. However, it should be borne in mind that no matter how detailed the foregoing may be described in the invention, the embodiment may be practiced in many ways and its interpretation should be consistent with the appended claims and any equivalents thereof. As used herein, the term roughly refers to a numerical value, including, for example, whole numbers, fractions and percentages, whether explicitly stated or not. The term approximately generally refers to a range of numerical values (eg, +/- 510% of a specified range) that would be considered by one of ordinary skill in the art to be equivalent to a specified value (eg, having the same function or result). When terms such as at least and approximately precede a list of numerical values or ranges, those terms modify all values or ranges presented in the list. In some cases, the term approximately may include numerical values rounded to the nearest significant figure. CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is selected from N and CR ^x ; V, Y and Z are selected from (i), (ii) or (iii): (i) V represents C(O); Y is selected from C(O) and CR ^j R ^k and Z is selected from C(O) and CR ^j R ^k ; (ii) V is selected from the chemical bond, C(O) and CR ^f R ^g ; Y is C(O) and Z is selected from C(O) and CR ^j R ^k or (iii) V is selected from a chemical bond, C(O) and CR ^f R ^g ; Y is selected from C(O) and CR ^j R ^k and Z is C(O); L represents -(CH ₂ ) _n -; n is 0, 1 or 2, wherein each methylene unit in L is optionally replaced by one C ₁ -C ₆ alkyl, and if n is 2 then one methylene unit in L is optionally replaced by oxygen; - 49 042925 in each case R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , Ri , R ^j , R ^k and R ^x are independently selected from hydrogen, halogen and C ₁ - C ₆ -alkyl; ring A is selected from C ₃ -C ₁₀ -cycloalkyl, 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and 5-10 membered heteroaryl containing from 1 to 3 heteroatoms, selected from nitrogen, oxygen and sulfur, wherein ring A is optionally substituted with one or more W; each W is independently selected from halogen, -OR, -CN, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected of nitrogen, oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where the optionally substituted W group may be substituted by one or more R ¹ ; each R ¹ is independently selected from halogen, -OR, -CN, -NO ₂ , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, -(CH ₂ ) _m (C ₃ -C ₁₀ cycloalkyl), - (CH ₂ ) _m (3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl); each R is independently selected from hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl and phenyl and each m is independently 0 or 1. 2. The compound according to claim 1, where Y is selected from C(O) and CR ^j R ^k ; n represents 0; R ^a is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl; ^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh ,} Ri, Rj, ^Rk and ^Rx are each hydrogen; ring A is a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W; each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl, wherein the optionally substituted W group may be substituted by one or more R ¹ ; each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _m (3-10 membered heterocyclyl containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (C ₆ aryla); each R represents phenyl and each m represents 1. 3. A compound according to claim 1 or 2, where V is selected from C(O) and CR ^f R ^g ; X represents N; Y represents C(O); n represents 0; R ^a represents hydrogen; ^Rb , ^Rc , ^Rd , Re, ^Rf , ^Rg , ^{Rh ,} Ri, Rj, ^Rk and ^Rx are each hydrogen; ring A is a 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, where ring A is optionally substituted with one or more W; each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur , and optionally substituted phenyl, wherein the optionally substituted W group may be substituted by one or more R ¹ ; each R ¹ is independently selected from halogen, -OR, -CN and -(CH ₂ ) _m (phenyl); each R represents phenyl and each m represents 1. 4. A compound according to any one of claims 1 to 3, where L is selected from -(CH ₂ ) ₀ -, -CH ₂ -, -CH ₂ CH ₂ - and -CH2CH(CH3)-. 5. A compound according to any one of claims 1 to 4, where n is 0. 6. A compound according to any one of claims 1-5, where the compound has formula (II’-a) N (N'-a) or a pharmaceutically acceptable salt thereof. - 50 042925 7. A compound according to any one of claims 1-5, where the compound has formula (II’-b) or a pharmaceutically acceptable salt thereof. 8. A compound according to any one of claims 1-5, where the compound has formula (II’-c) or a pharmaceutically acceptable salt thereof. 9. A compound according to any one of claims 1-5, where the compound has formula (II’-d) or a pharmaceutically acceptable salt thereof. 10. A compound according to any one of claims 1-5, where the compound has formula (II’-e) or a pharmaceutically acceptable salt thereof. 11. A compound according to any one of claims 1-5, where the compound has formula (II’-g) or a pharmaceutically acceptable salt thereof. 12. A compound according to any one of claims 4-11, where ring A is selected from C ₃ -C ₁₀ -cycloalkyl, 3-10 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl and 5- A 10-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein ring A is optionally substituted by one or more W. 13. A compound according to any one of claims 1, 2 and 4-12, wherein ring A is an optionally substituted 5-6 membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. 14. A compound according to any one of claims 1 to 13, wherein ring A is an optionally substituted 5-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. 15. A compound according to any one of claims 1 to 14, wherein ring A is an optionally substituted thiazolyl or pyrazolyl. 16. A compound according to any one of claims 1 to 15, where the compound has formula (III) or a pharmaceutically acceptable salt thereof. 17. A compound according to any one of claims 1-6 and 12-16, where the compound has formula (III-a) or a pharmaceutically acceptable salt thereof. - 51 042925 18. A compound according to any one of claims 1-5, 7 and 12-16, where the compound has formula (III-b) or a pharmaceutically acceptable salt thereof. 19. A compound according to any one of claims 1-5, 8 and 12-16, where the compound has formula (III-c) or a pharmaceutically acceptable salt thereof. 20. A compound according to any one of claims 1 to 15, where the compound has formula (IV) or a pharmaceutically acceptable salt thereof. 21. A compound according to any one of claims 1-6, 12-15 and 20, where the compound has formula (IV-a) or a pharmaceutically acceptable salt thereof. 22. A compound according to any one of claims 1-5, 7, 12-15 and 20, where the compound has formula (IV-b) or a pharmaceutically acceptable salt thereof. 23. A compound according to any one of claims 1-5, 8, 12-15 and 20, where the compound has formula (IV-c) or a pharmaceutically acceptable salt thereof. 24. The connection according to any one of claims 4-23, where in each case Ra, R ^b , Rc, R ^d , R ^e , R ^f , R ^g , R ^h , R R j, R ^k and R ^x are independently selected from hydrogen, halogen and C1-C ₆ alkyl. 25. A compound according to any one of claims 1, 2 and 4-23, where Ra is selected from hydrogen, halogen and C ₁ -C ₆ -alkyl. 26. The compound according to any one of claims 1 to 25, wherein in each case R ^b , Rc , R ^d , R ^e , R ^f , R ^g , R ^h , R R j , R ^k and R ^x each represent hydrogen. 27. A compound according to any one of claims 1 to 26, wherein Ra represents hydrogen. 28. A compound according to any one of claims 4 to 27, wherein each W is independently selected from halogen, -OR, -CN, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3 -10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted phenyl and optionally substituted 5-10-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. 29. A compound according to any one of claims 1 to 28, wherein each W is independently selected from halogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted C ₃ -C ₁₀ -cycloalkyl, optionally substituted 3-10 membered heterocyclyl, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl. 30. A compound according to any one of claims 1 to 29, wherein each W is independently selected from halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, optionally substituted 5-6 membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted phenyl. 31. A compound according to any one of claims 1 to 30, wherein each W is independently selected from chlorine, tert-butyl, cyclohexyl, 2-benzylpiperidinyl, phenyl, 3-cyanophenyl, 3-chlorophenyl, 2-phenoxyphenyl and 3-(azetidine-1- ylmethyl)phenyl. 32. A compound according to any one of claims 4 to 31, wherein each R ¹ is independently selected from halogen, -OR, -CN, -NO ₂ , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, -( CH ₂ ) _m (C ₃ -C ₁₀ -cycloalkyl), -(CH ₂ ) _m (3-10-membered heterocyclyl containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl). - 52 042925 33. The compound according to any one of claims 1 and 4-32, where each R ¹ is independently selected from halogen, -OR, -CN, -(CH ₂ ) _m (3-6 membered heterocyclyl containing from 1 to 3 heteroatoms , selected from nitrogen, oxygen and sulfur) and -(CH ₂ ) _m (phenyl). 34. A compound according to any one of claims 1 to 33, wherein each R ¹ is independently halogen, -OR, -CN and -(CH ₂ ) _m (phenyl). 35. A compound according to any one of claims 1 and 4-34, wherein each R is independently selected from hydrogen, C ₁ -C ₆ alkyl and phenyl. 36. A compound according to any one of claims 1 to 35, wherein each R represents phenyl. 37. A compound according to any one of claims 1 to 36, wherein each m is 1. 38. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein V is selected from a chemical bond and CR ^f R ^g ; X is selected from N and CR ^x ; Y is selected from a chemical bond, carbonyl (C=O) and CRjR ^k ; Z is selected from carbonyl (C=O) and CRjR ^k ; L is -(CH ₂ ) _n -, n=0, 1, 2 or 3, where if n is 2 or 3 then L can optionally be replaced or interrupted by one or two C ₁ -C ₆ -alkyl and/or heteroatoms selected from nitrogen, oxygen and sulfur; R ^a and R ^x represent hydrogen; one of R ^b and R ^c is hydrogen, and the other is selected from hydrogen, C 1 -C 6 linear or branched alkyl groups and C ₁ -C ₆ linear or branched heteroalkyl groups, optionally substituted with R ¹ ; one of R ^d and R ^e is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ; one of ^Rf and ^Rg is hydrogen and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1- _C6 linear or branched heteroalkyl groups optionally substituted with ^R1 , or alternatively ^Rf and ^Rg combined to form carbonyl; one of R ^h and R ⁱ is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1- _C6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ; one of Rj and ^Rk is hydrogen, and the other is selected from hydrogen, C1-C6 linear or branched alkyl groups and C1-C6 linear or branched heteroalkyl groups, optionally substituted with R ¹ ; ring A is selected from 5-10 membered cycloalkyl groups, 5-10 membered heterocycloalkyl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, and 5-10 membered heteroaryl groups containing from 1 to 5 heteroatoms , selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one W group; W is selected from hydrogen, halogen, cyano groups, C1- _C6 alkyl groups, C1- _C6 alkylether groups, 3-10 membered cycloalkyl groups, 3-10 membered heterocycloalkyl groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, 6-10 membered aryl and 5-10 membered heteroaryl groups containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, the groups being unsubstituted or substituted by at least one R ¹ group , which may be the same or different; And R ¹ is independently selected from hydrogen, halogen, hydroxyl groups, cyano groups, amide groups, amino groups, C1- _C6 alkyl groups, C1- _C6 alkyl ether groups, C1- _C6 alkylamino groups, C _r C ₆ alkyl alcohol groups, C ₃ -C ₆ -cycloalkyl groups, S(O) ₂ groups and trifluoromethyl and trifluoromethylether groups, where any heteroalkyl group is an alkyl group in which one or more carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen and sulfur. - 53 042925 39. The connection according to claim 38, where ring A is selected from A N- ⁷ Oy LI A exo N y AU ^-n ID 00 S CO A N-0 3 Ν 0 0 rU N-N A 00 Uy Oy OX 0 OXh 000 ^x Ν chААу fU 000 NN хИ ON nOO Ν^Ο ^N Дч Λ 00 0 0 00 N JAN _s CX^ 00 N NN <°I N-0/ 00 0 О CI°0 00 N NN 44 ζ ^Ν 0 X ON vs OCy OCT N A A zx co N ^J Ny^ Os Z'N XOy A 0 A /=\ 0 0 O\__/N—| 07 N Α0-Ν . (O oo NO 0Ny OY 0 oryx Χχχ X Ν.0Ν yO Ν0 1 NH . 70/ AND N0 G NH 5/0, wherein these groups are optionally replaced by at least one W group. 40. A compound according to claim 38 or 39, where W is selected from hydrogen, halogen, cyano groups, Ci-Cb-alkyl groups, Ci-Cb-alkylether groups, 3-10 membered cycloalkyl groups, 3-10 membered heterocycloalkyl groups, containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, 6-10 membered aryl groups and 5-10 membered heteroaryl groups containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, while the groups are unsubstituted or substituted by at least one R ¹ group, which may be the same or different. 41. A compound according to any one of claims 38 to 40, wherein R ¹ is independently selected from hydrogen, halogen, cyano groups, amide groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkyl ether groups and trifluoromethyl and trifluoromethyl ether groups . 42. Connection selected from Connection number Structure Chemical name 1-1S 0^-° (8)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-1R (R)-8-(5-cyclohexylthiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile - 54 042925 *(8)-8-(5-(tert-butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile *(K)-8-(5-(tert -butyl)-4-chlorothiazol2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile (8)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[ 1,2-a]pyrazin-2carbonitrile (K)-8-(4-chloro-5-cyclohexylthiazol-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile (K)-8-(5 -(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2 carbonitrile 1-4S (8)-8-(5-(3-cyanophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2 carbonitrile 1-5R (C)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-5S (8)-8-(5-(3-chlorophenyl)pyrimidin-2yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile - 55 042925 1-6R ...i Co (R)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-6S / (8)-8-(5-(3-cyanophenyl)thiazol-2-yl)9-oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7R /c>o (R)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-7S (8)-8-(5-(3-chlorophenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-11R χθθΗ (R)-8-(5 -(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-11S Ο Ν—° _χ ,G—/ (8)-8-(5-(3-chlorophenyl)isoxazol-3 yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-12S,R ΎίΟ° (4aS, 8aR)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12R,S x^y>O th (4a^8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile - 56 042925 1-12R,R (4aR, 8aR)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 1-12S,S (4a8,8a8)-7-(5-cyclohexylthiazol-2yl)-8-oxooctahydro-2,7-naphthyridine2(1H)-carbonitrile 2-1R (R)-8-(5-cyclohexylthiazol-2-yl)-4,9dioxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1S (8)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 3-1R of coy (R)-8-(5-cyclohexylthiazol-2-yl)-4oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 4-lS,S xouJOAl А X ^x Or s ^z H (4а8,8а8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 4-lS,R AO-TOUE Y V x \__/ (4aS, 8aR)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 4-lR,S G-Ι ^s 1 x ^H 1 (4aAl8a8)-7-(5-cyclohexylthiazol-2yl)-octahydro-2,7-naphthyride in-2(1H)carbonitrile 5-lR,R ChAO (3K7aK)-2-(5-cyclohexylthiazol-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile - 57 042925 5-lS,S J ₅ YJ (Za8,7a8)-2-(5-cyclohexylthiazol-2yl)-3-oxooctahydro-5H-pyrrolo[3,4c]pyridine-5-carbonitrile 5-2R,R (3aR,7aR)-2-(5-(3cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyridin-5-carbonitrile 5-2S,S (3aS,7aS)-2-(5-(3- cyanophenyl)pyrimidin-2-yl)octahydro-5H-pyrrolo[3,4-c]pyr idin-5-carbonitrile 6-1R O nA T c >—Y O N-Z\ Cl (R)-8-(5-(τpeτ-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 6-1S 0 rY s / nA if ¥ Av 0 Νγ ^x Cl (8)-8-(5-(tert-butyl)-4-chlorothiazol-2yl)-6,9-d ioxooctahydro-2Hpyrazino[1,2- a]pyrazine-2carbonitrile 1-14S XqAAA-O *(8)-9-oxo-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-14R *(R)-9-oκco-8-(5-phenylthiazol-2yl)octahydro-2H-pyrazino[1,2a]pyrazine-2-carbonitrile hdl (R)-8-(5-(τpeτ-bytyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-15S 4 Υί ί γΑ (8)-8-(5-(tert-butyl)thiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile - 58 042925 1-113S d Сн ό *(8)-9-oxo-8-(5-(2-phenoxyphenyl)thiazol-2-yl)octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-113R Z-o *(R)-9-okco-8-(5-(2- phenoxyphenyl)thiazol-2-yl)octahydro-2H-pyrazino[1,2-a]pyrazin-2-carbonitrile 1-114R /0 (R)-9-oκco-8-(5-(2-φenoκciφenyl)1Н-pyrazol-3-yl)-octahydro-2Нpyrazino[1,2-а]-pyrazin-2carbonitrile 1-114S c ο N—™ )=^ ^N 'XX 1 (8)-9-oxo-8-(5-(2-phenoxy-phenyl)1 H-pyrazol-3 -yl)-octahydro-2Hpyrazino[1 ,2-a]-pyrazine-2carbonitrile 1-115R XX (R)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile 1-115S '^cC^R (8)-8-(5-(3 -(azetidin-1 -ylmethyl)phenyl)thiazol-2-yl)-9oxooctahydro-2H-pyrazino[1,2a]pyrazin-2-carbonitrile - 59 042925 1-116R RRzh ^)-8-(5-(tert-butyl)-4-chloro-thiazol2-yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-116S Ύη Cl (8)-8-(5-(tert-butyl)-4-chloro-thiazol-2yl)-9a-fluoro-9-oxo-octahydro-2Hpyrazino[1,2-a]-pyrazin-2carbonitrile 1-117R Ο Ν—Ύ\ /---- ......ν>-υ (R)-8-(5-cyclohexylthiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-117S Ο/---, (8)-8-(5-cyclohexylthiazol-2-yl)-9amethyl-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118R,S Ρ 1 ^Ν 1 4 / \ Υ Υ /^ ^Ν \ / Ο nJ ⁴ - ¹ (R)-8-(5-((S)-2-benzylπpipiridin-1 yl)thiazol-2-yl )-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazine-2carbonitrile 1-118R,R :: ΐ Υ Υ Υ У-N) (R)-8-(5-((R)-2-benzylπpipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro-2Hpyrazino[1,2-a]pyrazin-2carbonitrile 1-118S,S Ρ ί ^Ν 1 / \ Υ Υ Υ ^Ν \ J ο ν-Δ \' (8)-8-(5-((8)-2-benzylpiperidin-1 yl)thiazol-2-yl) -9-oxooctahydro-2Hpyrazino[1,2-a]pyrazine-2carbonitrile 1-118S,R Ο \ νΥ Υ Υ ΥΎ J Ο Ν—U ⁴ —' (S)-8-(5-((R)-2-benzylπpipipipiridin-lyl)thiazol-2-yl)-9-oxooctahydro- 2Hpyrazino[1,2-a]pyrazine-2carbonitrile or a pharmaceutically acceptable salt thereof. 43. Pharmaceutical composition containing a compound according to any one of p. 1-42 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 44. A method of inhibiting ubiquitin-specific peptidase 30 in humans, comprising administering a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43. 45. A method of treating a disease, disorder or condition associated with ubiquitin-specific peptidase 30, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43 . 46. A method of treating a neurodegenerative or neurological disease, disorder or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43. 47. A method of treating a disease, disorder or condition associated with mitochondrial dysfunction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 43. 48. The method according to any one of paragraphs 45-47, where the disease, disorder or condition is Parkinson's disease. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2