RU2839891C1 - Heteroaryl-substituted spiropiperidinyl derivatives and pharmaceutical applications thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: group of inventions relates to a compound of formula (I), (I), or a pharmaceutically acceptable salt thereof, or a compound selected from a group consisting of 1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-(2,2,2-trifluoroethoxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one; 1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(1-benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecane-2-one; rac-9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (S) -9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one; rac-9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; and (R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecane-2-one; or a pharmaceutically acceptable salt thereof, and also relates to a method of modulating leukotriene C4 synthase (LTC4S) activity in a subject, where the method involves administering to the subject a single dosage of 1–1000 mg for subject weighing 50–70 kg, the compound or a pharmaceutically acceptable salt thereof.

EFFECT: heteroaryl-substituted spiropiperidinyl derivatives and pharmaceutical applications thereof are disclosed.

7 cl, 1 tbl, 120 ex

Description

The present invention relates to novel heteroaryl-substituted spiropiperidinyl compounds useful as leukotriene C4 synthase (LTC4S) inhibitors. The present invention also relates to pharmaceutical compositions containing said compounds, methods of using said compounds in the treatment of various diseases and disorders, and methods of preparing said novel compounds.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof and their use for inhibiting LTC4S. Accordingly, the compounds of the present invention may be useful in the treatment of diseases and/or disorders mediated by LTC4S. Such diseases and/or disorders typically include respiratory diseases/disorders, inflammation and/or disease/disorders characterized by an inflammatory component. The present invention further relates to pharmaceutical compositions comprising said heteroaryl-substituted spiropiperidinyl compounds of formula (I), methods of using said compounds in the treatment of various diseases and disorders, and methods for preparing said new compounds.

BACKGROUND OF THE INVENTION

Cysteinyl leukotrienes (cys-LTs), leukotriene C4 (LTC4) and its metabolites, LTD4 and LTE4, are proinflammatory lipid mediators in asthma and other inflammatory diseases. They are generated via the 5-lipoxygenase/LTC4 synthase (LTC4S) pathway and act through at least two different G protein-coupled receptors. Leukotriene (LT) C ₄ synthase (LTC4S) catalyzes the conjugation reaction between the fatty acid LTA ₄ and GSH to form the proinflammatory LTC ₄ , an important mediator of asthma.

There are many diseases/disorders that are inflammatory in nature or have an inflammatory component. One of the major problems with existing treatments for inflammatory conditions is the lack of efficacy and/or prevalence of side effects.

Asthma is a chronic inflammatory disease that affects 6% to 8% of the adult population in industrialized countries. The incidence is even higher in children, accounting for about 10% in most countries. Asthma is the most common cause of hospitalization in children under fifteen years of age. Treatment regimens for asthma depend on the severity of the condition. Mild forms of the disease are either left untreated or treated only with inhaled beta-agonists. Patients with more severe asthma are usually treated with anti-inflammatory compounds on a regular basis.

There is a significant gap in the treatment of asthma, at least in part due to the perceived risks of existing maintenance therapies (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, leading to unnecessary morbidity and mortality. LTRAs have been developed as an alternative to steroids. These drugs can be given orally, but are significantly less effective than inhaled steroids and generally do not adequately control airway inflammation. This combination of factors has resulted in at least 50% of all asthma patients being inappropriately treated.

A similar situation of undertreatment exists with respect to allergic disorders, where drugs are available to treat a number of common conditions but are underused because of their pronounced side effects. For example, rhinitis, conjunctivitis, and dermatitis may all have an allergic component, but may also occur in the absence of an underlying allergy. Indeed, nonallergic conditions in this class are often more difficult to treat.

Other inflammatory disorders that may be indicated include chronic obstructive pulmonary disease (COPD), which is a common disorder affecting 6% to 8% of the world's population. The disease is potentially fatal, and the morbidity and mortality of the condition are significant. There is currently no known pharmacologic treatment that can modify the course of COPD; pulmonary fibrosis (this is less common than COPD but is a serious disorder with a very poor prognosis); inflammatory bowel disease (a group of disorders with high morbidity - currently only symptomatic treatments are available for these disorders); rheumatoid arthritis and osteoarthritis (common, disabling inflammatory disorders of the joints - currently no cure and only moderately effective symptomatic treatments exist for these conditions); diabetes, a disease affecting more than 3% of the world's population and increasing in prevalence, causing considerable morbidity and mortality; and cardiovascular disease.

Inflammation is also a common cause of pain. Inflammatory pain can arise from many causes, such as infection, surgery, or other trauma. Moreover, some malignancies are characterized by an inflammatory component that exacerbates patients’ symptoms. Inflammation may also be involved in cancer development, since leukotrienes are involved in cancer cell proliferation and in increasing cancer cell survival. Thus, new and/or alternative treatments for respiratory and/or inflammatory disorders would be beneficial for all of the above patient groups. In particular, there is a real and significant unmet clinical need for an effective anti-inflammatory drug that can treat inflammatory disorders, in particular asthma and atopic dermatitis, without significant or expected side effects.

Therefore, inhibition of LTC4S may be useful in the treatment of cys-LT-associated inflammatory diseases such as asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis, chronic obstructive pulmonary disease.

For reviews on cysteine leukotrienes and LTC4, see B. Lam et al. Clinical and Experimental Allergy Reviews, 2004, 4, 89-95; B. Lam et al., Prostaglandins & Other Lipid Mediators, 2002, 68-69, 511-520; H.-E. Claesson et al., Journal of Internal Medicine 1999, 245, 205-277

BRIEF DESCRIPTION OF THE INVENTION

There remains a need for new treatments and therapies for diseases or disorders mediated by LTC4S. The present invention provides compounds, their pharmaceutically acceptable salts, pharmaceutical compositions thereof, and combinations thereof that are LTC4S inhibitors. The present invention further provides methods for treating, preventing, or reducing the severity of a disease and/or disorder mediated by LTC4S, comprising administering to a subject in need thereof an effective amount of an LTC4S inhibitor.

Various embodiments of the present invention are described herein.

In certain aspects, this document provides a compound of formula I or a pharmaceutically acceptable salt thereof,

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is phenyl optionally substituted with one or more halogen-containing substituents;

R ² represents H or fluorine;

X ¹ is CH ₂ or O;

R ⁴ is a mono- or bicyclic heteroaryl optionally substituted with one or more R3 substituents;

wherein each R ³ is independently selected from C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10-membered heteroaryl, 4-10-membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , wherein R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halo-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl;

provided that if R ² is F, then X ¹ is CH ₂ .

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in formula (I) or its subformulas, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is useful in the treatment of diseases and/or disorders associated with LTC4S activity.

In another aspect, the present invention provides a combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound as defined in formula (I) or its subformulas, or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents.

Another aspect of the present invention relates to a method of modulating LTC4S activity, more particularly to inhibiting LTC4S activity. The method comprises administering to a subject in need thereof a compound of formula (I) or its subformulas or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method for treating a disease or disorder selected from respiratory diseases/disorders, inflammation and/or diseases/disorders characterized by an inflammatory component, such as allergic disorders, asthma, wheezing in children, chronic obstructive pulmonary disease, aspirin-induced respiratory disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease and usual interstitial pneumonia), ear, nose and throat diseases (e.g. sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media and allergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis, eczema and chronic urticaria), rheumatic diseases (eg, rheumatoid arthritis, arthrosis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (eg, Henoch-Schonlein purpura, Loeffler syndrome and Kawasaki disease), cardiovascular diseases (eg, atherosclerosis, cerebrovascular disease, acute ischemic heart disease and treatment after myocardial infarction), gastrointestinal diseases (eg, eosinophilic gastrointestinal diseases, inflammatory bowel disease, irritable bowel syndrome, colitis, abdominal and gastric bleeding), urological diseases (eg, glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome and nephrotoxicity), central nervous system diseases (eg, cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing), endocrine diseases (eg, autoimmune thyroiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, kwashiorkor edema, dysmenorrhea due to burn oxidative damage, polytrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis, bacterial infections (eg, Helicobacter pylori, Pseudomonas aerugiosa, or Shigella dysenteriae), fungal infections (eg, vulvovaginal candidiasis), viral infections (eg, hepatitis, meningitis, parainfluenza, and respiratory syncytial virus), hypereosinophilic syndrome, and malignancies (eg, Hodgkin's lymphoma, leukemia (eg, eosinophilic leukemia and chronic obstructive pulmonary disease), myelogenous leukemia), mastocytosis, polycythemia vera and ovarian carcinoma).

In particular, the compounds of the present invention may be useful in the treatment of allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease. In one particular embodiment, the compounds of the present invention are useful for the treatment of asthma. In another particular embodiment, the compounds of the present invention are useful in the treatment of atopic dermatitis or chronic urticaria.

Another aspect of the present invention relates to the use of a compound of formula (I) or its subformulas or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder selected from respiratory diseases/disorders, inflammation and/or diseases/disorders characterized by an inflammatory component, such as allergic disorders, asthma, wheezing in children, chronic obstructive pulmonary disease, aspirin-induced respiratory disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease and usual interstitial pneumonia), ear, nose and throat diseases (e.g. sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media and allergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis, eczema and chronic urticaria), rheumatic diseases (eg, rheumatoid arthritis, arthrosis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (eg, Henoch-Schonlein purpura, Loeffler syndrome and Kawasaki disease), cardiovascular diseases (eg, atherosclerosis, cerebrovascular disease, acute ischemic heart disease and treatment after myocardial infarction), gastrointestinal diseases (eg, eosinophilic gastrointestinal diseases, inflammatory bowel disease, irritable bowel syndrome, colitis, abdominal and gastric bleeding), urological diseases (eg, glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome and nephrotoxicity), central nervous system disorders (e.g., cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing), endocrine disorders (e.g., autoimmune thyroiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, kwashiorkor edema, burn-induced dysmenorrhea, oxidative damage, polytrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis, bacterial infections (e.g., Helicobacter pylori, Pseudomonas aerugiosa, or Shigella dysenteriae), fungal infections (e.g., vulvovaginal candidiasis), viral infections (e.g., hepatitis, meningitis, parainfluenza, and respiratory syncytial virus), hypereosinophilic syndrome, and malignancies (e.g., lymphomas Hodgkin's disease, leukemia (eg, eosinophilic leukemia and chronic myelogenous leukemia), mastocytosis, polycythemia vera, and ovarian carcinoma).

The present invention also provides a compound of formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from respiratory diseases/disorders, inflammation, and/or diseases/disorders characterized by an inflammatory component, such as allergic disorders, asthma, wheezing in children, chronic obstructive pulmonary disease, aspirin-induced respiratory disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, and usual interstitial pneumonia), ear, nose and throat diseases (e.g. sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media, and allergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis, eczema, and chronic urticaria), rheumatic diseases (e.g., rheumatoid arthritis, arthrosis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (e.g., Henoch-Schonlein purpura, Loeffler syndrome, and Kawasaki disease), cardiovascular diseases (e.g., atherosclerosis, cerebrovascular disease, acute ischemic heart disease, and treatment after myocardial infarction), gastrointestinal diseases (e.g., eosinophilic gastrointestinal diseases, inflammatory bowel disease, irritable bowel syndrome, colitis, abdominal and gastric bleeding), urological diseases (e.g., glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), central nervous system disorders (e.g., cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and sleep-disordered breathing), endocrine disorders (e.g., autoimmune thyroiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, kwashiorkor edema, burn-induced dysmenorrhea, oxidative damage, polytrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis, bacterial infections (e.g., Helicobacter pylori, Pseudomonas aerugiosa, or Shigella dysenteriae), fungal infections (e.g., vulvovaginal candidiasis), viral infections (e.g., hepatitis, meningitis, parainfluenza, and respiratory syncytial virus), hypereosinophilic syndrome, and malignancies (e.g., Hodgkin's lymphoma, leukemia (eg, eosinophilic leukemia and chronic myelogenous leukemia), mastocytosis, polycythemia vera, and ovarian carcinoma).

DETAILED DESCRIPTION OF THE INVENTION

Thus, the present invention provides a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is phenyl optionally substituted with one or more halogen-containing substituents;

R ² represents H or fluorine;

X ¹ is CH ₂ or O;

R ⁴ is a mono- or bicyclic heteroaryl optionally substituted with one or more R3 substituents;

wherein each R ³ is independently selected from C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10-membered heteroaryl, 4-10-membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , wherein R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halo-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl;

provided that if R ² is F, then X ¹ is CH ₂ .

Unless otherwise specified, the term "compounds of the present invention" refers to compounds of formula (I) or its subformulas and their salts, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers and isotopically labeled compounds (including deuterium substituted ones), as well as naturally occurring fragments.

For the purpose of interpreting this description, the following definitions shall apply unless otherwise stated and, where appropriate, terms used in the singular shall also include the plural and vice versa.

It should be noted that the singular forms used in this document and in the appended claims include the plural forms unless the context clearly requires otherwise. Thus, for example, a reference to a "compound" includes a reference to one or more compounds, etc.

Definitions

The term "C" as used in this document_1-6"alkyl" means a straight or branched chain hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, containing from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. The term "C_1-2"alkyl" should be construed accordingly. Examples C_1-6alkyl include, but are not limited to, methyl, ethyl,n-propyl, 1-methylethyl (isopropyl),n-butyl,n-pentyl and 1,1-dimethylethyl (rubs-butyl).

As used herein, the term "C _1-6 alkoxy" refers to a radical of the formula -OR _a , wherein R _a is a C _1-6 alkyl radical, as generally defined above. Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

As used herein, the term " _C3-7 cycloalkyl" refers to a stable mono- or bicyclic saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing from three to seven carbon atoms. _C3-6 cycloalkyl should be construed similarly. Cycloalkyl groups may include bridged rings as well as spirocyclic rings. Examples of _C3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

"Halogen" refers to bromine, chlorine, fluorine or iodine.

As used herein, the term "halo-C _1-6 alkyl" refers to a C _1-6 alkyl radical as defined above substituted with one or more halogen-containing radicals as defined above. Examples of halo-C _1-6 alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

As used herein, the term "halo-C _1-6 alkoxy" refers to a C _1-6 alkoxy radical, as defined above, substituted with one or more halogen-containing radicals, as defined above. Examples of halo-C _1-6 alkyl include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy, and 2,2,2-trifluoroethoxy.

As used herein, the term “heterocyclyl” refers to a heterocyclic group which is saturated or partially saturated, and is preferably a monocyclic or polycyclic ring (in the case of a polycyclic ring, in particular a bicyclic, tricyclic or spirocyclic ring); and contains from 3 to 24, more preferably from 4 to 16, most preferably from 5 to 10 and most preferably 5 or 6 ring atoms; wherein one or more, preferably from one to four, especially one or two ring atoms are a heteroatom (the remaining ring atoms are therefore carbon atoms). The term “heterocyclyl” excludes heteroaryl. The heterocyclic group may be attached to a heteroatom or a carbon atom. Heterocyclyl may include fused or bridged rings, as well as spirocyclic rings.

In one embodiment, the heterocyclyl is a 5-7-monocyclic ring containing 1 or 2 heteroatoms. In another embodiment, the heterocyclyl is 6-10-spiroheterocyclyl.

Examples of heterocycles include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolan, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. A non-limiting example of a spiroheterocyclyl is azaspiro[2.3]hexanyl. A non-limiting example of a bridged heterocyclic ring is bicyclo[1.1.1]pentanyl.

As used herein, the term "heteroaryl" refers to a 5- to 14-membered monocyclic or bicyclic aromatic ring system containing from 1 to 8 heteroatoms. Each heteroatom is independently selected from O, N, or S, where S and N may be oxidized to various oxidation states. Typically, heteroaryl is a 5- to 10-membered ring system (e.g., 5- or 6-membered monocycle or 8-10-membered bicycle).

Typically, a monocyclic heteroaryl contains from 5 or 6 ring members selected from carbon atoms and from 1 to 4 heteroatoms and. Representative monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2,5-diazolyl, oxa-3,4-diazolyl, thia-2,3-diazolyl, thia-2,4-diazolyl, thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl.

When a heteroaryl is substituted with a hydroxyl group, the compounds can exist in various tautomeric forms. One non-limiting example of tautomerization is the following:

As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Non-limiting examples include phenyl, naphthyl. In a preferred embodiment, aryl is phenyl.

Various embodiments of the present invention are described herein. It should be understood that the features indicated in each embodiment can be combined with other indicated features to obtain additional embodiments of the present invention.

In embodiment 1, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described above.

In embodiment 2, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to embodiment 1, wherein R ⁴ is selected from the group consisting of pyrimidinyl, pyrazinyl, triazolyl, triazinyl, pyridinyl, pyridine oxide, pyrimidine oxide, pyrazine oxide, quinolinyl, quinazolinyl, quinoxalinyl, indazolyl, pyrazolopyrimidinyl, pyridopyrazinyl, triazolopyridazinyl, benzooxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, oxazolyl and thiazolyl, each of which is optionally substituted with one or more R ³ substituents;

wherein each R ³ is independently selected from C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10-membered heteroaryl, 4-10-membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , wherein R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halo-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl; and wherein

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, C _3-7 cycloalkyl-C _1-6 alkenyl are optionally substituted with one or more substituents selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with C _1-6 alkyl or halo-C _1-6 alkyl.

In embodiment 3, the present invention provides a compound of formula (I) according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from

where * denotes the point of attachment to the nitrogen atom of the spiropiperidinyl moiety; and

where n is an integer from 1 to 3; p is 1 or 2; s is an integer from 1 to 4; and R ^3a , R ^3b and R ^3c are independently selected from the group consisting of H, C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , wherein R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, _C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, C _3-7 cycloalkyl-C _1-6 alkenyl are optionally substituted with one or more substituents selected from C _1-6 alkyl, C _1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with C _1-6 alkyl or halo-C _1-6 alkyl; and wherein

R ^3d is selected from H, C _6-10 aryl, C _1-6 alkyl, halo-C _1-6 alkyl, C _3-6 cycloalkyl, 5- or 6-membered heteroaryl; and wherein said aryl, cycloalkyl, heteroaryl are further optionally substituted with one or more substituents independently selected from C _3-6 cycloalkyl, C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, halogen and halo-C _1-6 alkyl; or a pharmaceutically acceptable salt thereof.

In embodiment 4, the present invention relates to a compound according to any one of embodiments 1 to 3, wherein the compound is characterized by formula (II),

where R ^3a , R ^3b and R ^3c are independently selected from the group consisting of H, C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , where R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, _C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

In a particular aspect of this embodiment, at least one of R ^3a , R ^3b and R ^3c is not hydrogen.

In embodiment 5, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^3a is H; NH ₂ or hydroxy-C _1-3 alkyl;

R ^3b is selected from the group consisting of halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _3-7 cycloalkyl, OR ⁵ , 4-10 membered heterocyclyl, 5-10 membered heteroaryl, phenyl, and wherein said heterocyclyl, heteroaryl, phenyl and cycloalkyl are further optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, halogen and halo-C _1-6 alkyl; wherein

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, C _3-7 cycloalkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl or C _3-7 cycloalkyl is optionally substituted with one or more substituents independently selected from C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkoxy, halogen; and

R ^3c represents H or halogen.

In another aspect of embodiment 5, the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^4a is H or NH ₂ , -CH ₂ OH;

R ^3b is selected from the group consisting of halogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _3-7 cycloalkyl, OR ⁵ , 4-10-membered heterocyclyl selected from

where R ^3' is H, C _1-6 alkyl or halo-C _1-6 alkyl;

or R ^3b is a 5- to 10-membered heteroaryl selected from

; or

R ^3b is phenyl;

wherein said heterocyclyl, heteroaryl, phenyl and cycloalkyl are further optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, halogen and halo-C _1-6 alkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, C _3-7 cycloalkyl, phenyl, benzyl, 4-10 membered heterocyclyl selected from

or R ⁵ is phenyl, benzyl or pyridinyl;

wherein cycloalkyl, heterocyclyl, phenyl, benzyl and pyridinyl are optionally substituted with one or more substituents independently selected from halogen, C _1-6 alkyl, halo-C _1-6 alkyl and C _3-7 alkoxy; and

and R ^4c represents H or halogen.

In embodiment 6, the present invention relates to a compound according to any one of embodiments 1 to 3, wherein the compound is characterized by formula (III),

Where

where Y ¹ is N or CR ^3c , and where R ^3a , R ^3b and R ^3c are independently selected from the group consisting of H, C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , where R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, _C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

In a particular aspect of this embodiment, at least one of R ^3a , R ^3b and R ^3c is not hydrogen.

In one particular aspect of embodiment 6, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein R ^3a , R ^3b and R ^3c are independently selected from H, C _6-10 aryl, C _3-6 cycloalkoxy, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, OH, C _3-6 cycloalkyl, 5- or 6-membered heteroaryl, 5- to 10-membered heterocyclyl and NR ^a R ^b , wherein R ^a and R ^b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halo-C _1-6 alkyl or; and

wherein said aryl, heterocyclyl, heteroaryl, _C3-6 cycloalkyl, _C3-6 cycloalkoxy are further optionally substituted with one or more substituents independently selected from _C3-6 cycloalkyl, _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, halogen and halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof. In a particular aspect of this embodiment, if ^Y1 is ^CR3c ; at least one of ^R3a , ^R3b and ^R3c is not hydrogen. In yet another aspect of this embodiment, if ^Y1 is N, at least one of ^R3a and ^R3b is not hydrogen.

In another aspect of embodiment 6, the present invention relates to a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein Y ¹ is CR ^3c ; R ^3b and R ^3c are H; R ^3a is selected from the group consisting of H, halogen, halo-C _1-6 alkyl, C _3-6 cycloalkyl, halo-C _1-6 alkoxy, 5-10 membered heterocyclyl, NR ^a R ^b , wherein ^Ra and R ^b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl, or halo-C _1-6 alkyl; and wherein said cycloalkyl, heterocyclyl is further optionally substituted with one or more substituents independently selected from C _1-6 alkyl, C _1-6 alkoxy, halo-C _1-6 alkoxy, halogen and halo-C _1-6 alkyl.

In another aspect of embodiment 6, the present invention relates to a compound according to any of sub-embodiment 6 according to formula (III) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is CR ^3c .

In another aspect of embodiment 6, the present invention relates to a compound according to any one of sub-embodiment 6 according to formula (III) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N.

In embodiment 7, the present invention relates to a compound according to any one of embodiments 1 to 3, wherein the compound is characterized by formula (IV) or is represented by a pharmaceutically acceptable salt thereof,

and where

R ¹ is as defined in formula I,

Y ² is N or CR ^3b , and where

R ^3a , R ^3b , R ^3c and R ^3e are independently selected from H, C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , where R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, _C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

In one aspect of embodiment 7, the present invention relates to a compound according to formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ^3a , R ^3b , R ^3c and R ^3e are independently selected from H, C _6-10 aryl, C _3-6 cycloalkoxy, halo-C _1-6 alkyl, halo-C _1-6 alkoxy, OH, C _3-6 cycloalkyl, 5- or 6-membered heteroaryl, 5- to 10-membered heterocyclyl and NR ^a R ^b , wherein ^Ra and R ^b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halo-C _1-6 alkyl; and

wherein said aryl, heterocyclyl, heteroaryl, _C3-6 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-6 cycloalkoxy are further optionally substituted with one or more substituents independently selected from _C3-6 cycloalkyl, _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, halogen and halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof. In a particular aspect of this embodiment, if ^Y2 is ^CR3b ; at least one of ^R3a , ^R3b , ^R3c and ^R3e is not hydrogen. In yet another aspect of this embodiment, if ^Y2 is N, at least one of ^R3a , ^R3c and ^R3d is not hydrogen. Preferably, the pyridine or pyrazine ring is substituted at the R ^3b position (i.e., meta position).

In one aspect of embodiment 7 and sub-embodiments of embodiment 6, the present invention relates to a compound according to formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y ² is CR ^3b .

In another aspect of embodiment 7 and sub-embodiments of embodiment 6, the present invention relates to a compound according to formula (IV) or a pharmaceutically acceptable salt thereof, wherein Y ² is N.

In embodiment 8, the present invention relates to a compound according to any one of embodiments 1 to 3, wherein the compound is characterized by formula (V),

Where

Y ³ is N, NR ^3d or CR ^3a ;

Y ⁴ is N, NR ^3f or CR ^3b ;

Y ⁵ is N, NR ^3g or CR ^3c ;

Y ⁶ represents N, NR ^3h or CR ^3e ;

where R ^3a , R ^3b , R ^3c , R ^3e are independently selected from H, C _6-10 aryl, benzyl, C _1-6 alkyl, C _3-7 cycloalkoxy, hydroxy-C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkyl, halogen, halo-C _1-6 alkyl, OR ⁵ , CN, C(O)OC _1-6 alkyl, OH, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, 5-10-membered heteroaryl, 4-10-membered heterocyclyl, -C(O)NH ₂ and NR ^a R ^b , where R ^a and R ^b are independently H, C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl-C _1-6 alkyl or halogen-C _1-6 alkyl;

wherein said aryl, heterocyclyl, heteroaryl, _C3-7 cycloalkyl, _C3-7 cycloalkenyl, _C3-7 cycloalkoxy are further optionally substituted with one or more substituents independently selected from OH, CN, _C3-7 cycloalkyl, C3-7 cycloalkoxy, _NH2 , _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, hydroxy-C1-6 alkyl, _-SC1-6 alkyl; -S-(halo- _C1-6 alkyl), halogen, halo- _C1-6 alkyl, -C(O) _-C1-6 alkyl, phenyl optionally further substituted with halogen; and heteroaryl optionally substituted with halogen, C _1-6 alkyl, halo-C _1-6 alkyl or C _3-7 cycloalkyl;

R ⁵ is C _1-6 alkyl, halo-C _1-6 alkyl, hydroxy-C _1-6 alkyl, alkoxy-C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _3-7 cycloalkyl-C _1-6 alkyl, phenyl, benzyl, 4-10-membered heterocyclyl, 5-10-membered heteroaryl;

wherein phenyl, heterocyclyl and _C3-7 cycloalkyl, _C3-7 cycloalkyl- _C1-6 alkyl, _C3-7 cycloalkyl- _C1-6 alkenyl are optionally substituted with one or more substituents selected from _C1-6 alkyl, _C1-6 alkoxy, halogen, phenyl optionally further substituted with halogen; heterocyclyl optionally further substituted with _C1-6 alkyl or halo- _C1-6 alkyl;

where R ^3d , R ^3f , R ^3g , R ^3h are independently selected from H, C _6-10 aryl, C _1-6 alkyl, halo-C _1-6 alkyl, C _3-6 cycloalkyl, 5- or 6-membered heteroaryl;

and wherein said aryl, heteroaryl, _C3-6 cycloalkyl are further optionally substituted with one or more substituents independently selected from _C3-6 cycloalkyl, _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, halogen and halo- _C1-6 alkyl; or a pharmaceutically acceptable salt thereof.

The inner circle in the 5-membered ring shown in formula (V) means that the ring is an aromatic ring and therefore the members ^Y3 , ^Y4 , ^Y5 and/or ^Y6 must be chosen appropriately so as not to disturb the aromaticity.

In embodiment 9, the present invention relates to a compound according to embodiment 8 or a pharmaceutically acceptable salt thereof, wherein the moiety selected from the following

where * denotes the point of attachment to the nitrogen atom of the spiropiperidinyl moiety, and R ^3a , R ^3b , R ^3c , R ^4e and R ^4f are as defined in embodiment 8, and * denotes the point of attachment to the nitrogen atom of the spiropiperidinyl moiety.

In some aspects of embodiment 9, R ^3a is H; R ^3b or R ^3c is selected from phenyl optionally substituted with one or more halogen; C _1-6 alkyl; CN, halo-C _1-6 alkyl; C _3-6 cycloalkyl, 5-10 membered heterocyclyl; and NR ^a R ^b , wherein ^Ra and R ^b are independently H, C _1-6 alkyl, C _3-6 cycloalkyl, or halo-C _1-6 alkyl; wherein the heterocyclyl is optionally substituted with halo-C _1-6 alkyl or C _1-6 alkyl; and R ^3f is phenyl optionally substituted with one or more halogen.

In embodiment 10, the present invention relates to a compound of any of the preceding embodiments and sub-embodiments (e.g., a compound according to any of formulae (I) to (V)) or a pharmaceutically acceptable salt thereof, wherein R ¹ is phenyl optionally substituted with one or two substituents independently selected from F and Cl.

In one aspect of embodiment 10, the present invention provides a compound according to embodiment 10, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from

where * denotes the site of attachment of phenyl to the lactam nitrogen atom in the spiropiperidinyl moiety.

In embodiment 11, the present invention relates to a compound of any of the previous embodiments and sub-embodiments wherein X ¹ is CH ₂ , and R ² is F or H, or a pharmaceutically acceptable salt thereof. In one aspect of embodiment 11, R ² is H. In another aspect of embodiment 11, R ² is F; or a pharmaceutically acceptable salt thereof.

In embodiment 12, the present invention relates to a compound of any of the previous embodiments and sub-embodiments wherein X ¹ is O and R ² is H, or a pharmaceutically acceptable salt thereof.

In embodiment 13, the present invention relates to a compound of formula (I) according to embodiment 1, wherein the compound is selected from

1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide;

9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(2-(3,3-dimethylazetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(4-(trifluoromethyl)pyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(7-(trifluoromethyl)quinazolin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)azetidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-(pyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide;

4-(3-chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridin-1-oxide;

9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(4-(4-amino-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-5-fluoro-6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-amino-2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-(1,4-oxazepan-4-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-methyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(1H-pyrazol-1-yl)pyrimidine-2-carbonitrile;

1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-(1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-morpholino-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(dimethylamino)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-(4-chloro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-5-fluoro-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(4-amino-6-(4-fluoro-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(oxetan-3-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(4-(trifluoromethyl) -1H- pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one;

Synthesis of 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one;

rac -1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one;

4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide;

9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(4-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(hydroxyethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(4-propoxypyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -1-(3,4-difluorophenyl)-9-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-isopropoxypyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(2-hydroxyethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-((4,4-difluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-((tetrahydro-2H-pyran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac-9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -1-(3,4-difluorophenyl)-9-(6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

(S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

rac -ethyl-4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate;

(R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

( R )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;

( S )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;

( S )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;

( R )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;

rac -9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one;

rac -1-(3,4-difluorophenyl)-4-fluoro-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and

1-(3,4-difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; or a pharmaceutically acceptable salt thereof.

In embodiment 14, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(4-(trifluoromethyl) -1H- pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one;

(R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one,

(S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one;

9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and

9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 1, wherein the compound is 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 1, wherein the compound is 9-(2-amino-6-(4-(trifluoromethyl)-1H - pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one, or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 1, wherein the compound is (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 1, wherein the compound is (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 14, wherein the compound is 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 14, the present invention relates to a compound of formula (I) according to embodiment 14, wherein the compound is 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof.

Depending on the choice of starting materials and procedures, the compounds may be present in the form of one of the possible stereoisomers or as mixtures thereof, for example as pure optical isomers, or as a mixture of stereoisomers such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers and optically pure forms. Optically active ( R )- and ( S )-stereoisomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. If the compound contains a double bond, the substituent may have the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis- or trans-configuration. All tautomeric forms are also intended to be included.

As used herein, the terms "salt" or "salts" refer to an acid addition salt or a base addition salt of a compound of the present invention. "Salts" include, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or similar groups.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.

Organic acids with which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of metals from groups I-XII of the periodic table of elements. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

In another aspect, the present invention provides compounds of any of formulae (I)-(V) in the form of a salt which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucinate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate or xinafoate.

In another aspect, the present invention provides compounds of any of formulas (I)-(V) in the form of a sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper, isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine or tromethamine salt.

Any formula provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures depicted by the formulae provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be included in the compounds of the present invention include, for example, isotopes of hydrogen.

In addition, the inclusion of certain isotopes, in particular deuterium (i.e., ² H or D), may provide certain therapeutic advantages due to increased metabolic stability, such as increased half-life in vivo, or a reduction in the required dose, or an improvement in the therapeutic index or tolerability. It should be understood that deuterium in this context is considered as a substituent of the compound of formula (I). The concentration of deuterium can be determined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope and the natural abundance of said isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound is characterized by an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation for each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

Other examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, respectively. However, it should be understood that the present invention includes compounds in which one or more of any of the above isotopes are incorporated, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, compounds in which non-radioactive isotopes such as ² H and ¹³ C are present. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetics studies (e.g. using ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in the treatment of patients with radioactive isotopes. In particular, ¹⁸ F or a labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using a suitable isotopically labeled reagent in place of the unlabeled reagent previously used.

Pharmaceutical composition

As used herein, the term "pharmaceutical composition" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, fillers, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, coloring agents, and combinations thereof, which should be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22 ^nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting the activity of an enzyme or protein, or ameliorating symptoms, alleviating conditions, slowing or delaying the progression of a disease, or preventing a disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially alleviating, inhibiting, preventing, and/or ameliorating a condition or disorder or disease (i) mediated by LTC4S, or (ii) associated with LTC4S activity, or (iii) characterized by LTC4S activity (normal or abnormal); or (2) reducing or inhibiting LTC4S activity; or (3) reducing or inhibiting LTC4S expression . In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell or tissue or non-cellular biological material or medium, is effective to at least partially reduce or inhibit LTC4S activity or at least partially reduce or inhibit LTC4S expression.

As used in this document, the term "subject" refers to primates (e.g., humans - male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

As used herein, the terms "inhibit," "inhibition," or "inhibitory" refer to a reduction in the intensity or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the basal activity for a biological activity or process.

As used herein, the term "treat," "treating," or "treatment" of any disease or disorder refers to alleviating or ameliorating the disease or disorder (i.e., slowing or halting the progression of the disease or at least one of its clinical symptoms) or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be perceptible to the patient.

As used herein, the term "prevent," "preventing," or "preventing" any disease or disorder refers to the prophylactic treatment of a disease or disorder or the delay in the onset or progression of a disease or disorder.

As used herein, a subject is in "need" of treatment if the subject would benefit from such treatment from a biological, medical, or quality-of-life perspective.

As used herein, the singular and similar terms used in the context of the present invention (in particular, in the context of the claims) are to be construed as covering both the singular and the plural forms, unless otherwise indicated herein or clearly contradicted by context.

All methods described in this document may be performed in any suitable order unless otherwise indicated in this document or otherwise clearly contradicted by context. The use of any and all examples or introductory words preceding examples (e.g., "such as") provided herein are intended only to better explain the present invention and do not limit the scope of the present invention otherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention may be present in racemic or enantiomerically enriched form, such as in the ( R )-, ( S )-, or ( R,S )-configuration. In certain embodiments, each asymmetric atom is characterized by at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the ( R )- or ( S )-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in the cis- ( Z )- or trans- ( E )-form.

Accordingly, as used herein, a compound of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, such as substantially pure geometric ( cis or trans ) stereoisomers, diastereoisomers, optical isomers (antipodes), racemates, or mixtures thereof.

Any resulting mixtures of stereoisomers can be separated on the basis of physicochemical differences of the constituent components into pure or practically pure geometric or optical isomers, diastereoisomers, racemates, for example, by means of chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be separated into optical antipodes by known methods, for example, by separating their diastereomeric salts obtained using an optically active acid or base and isolating the optically active acidic or basic compound in free form. In particular, the basic moiety can thus be used to separate the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be separated by chiral chromatography, e.g. high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

Methods for synthesizing spiropiperidinyl derivatives of the present invention.

The agents of the present invention, for example compounds according to the definition of formula (I), wherein X1 is _CH2 and ^R2 is H, can be prepared by a sequence of reactions according to reaction schemes 1 and 2 below:

Scheme 1

where PG is a nitrogen protecting group (e.g. benzyl (Bn), carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC) and other well-known nitrogen protecting groups), and R ¹ is as defined in formula I, embodiment 1, and where R is a carboxylic acid protecting group, e.g. C _1-6 alkyl or benzyl.

In Method A, intermediate 9 is formed by reacting an N-protected piperidinone ( 1 ) with an appropriately substituted aniline ( 2 ), typically commercially available, to form intermediate 3 , which is reacted with a Grignard reagent (such as allyl magnesium bromide) to form intermediate 4. Cross metathesis of 4 with an appropriate acrylic acid ester yielded 5. Hydrogenation of 5 in the presence of a suitable catalyst such as palladium on carbon or Adams' catalyst yielded intermediate 6 , followed by deprotection of the carboxylic acid ( 7 ) and dehydration cyclization using a suitable reagent such as _SOCl2 . The spirocyclic lactam ( 8 ) thus formed can be deprotected to form intermediate 9.

Depending on the selection of the protecting groups for the amino group of piperidine and the carboxylic acid, the methods for removing the protecting group should be adapted according to the well-known methods (such as hydrogenation methods, acidic or basic methods for removing the protecting group). For example, methyl or ethyl ester, which is a protecting group for the carboxylic acid, can be removed by saponification, and tert-butyloxycarbonyl (Boc), which is a protecting group for the nitrogen atom of piperidine, can be removed by treatment with hydrochloric acid in a suitable solvent such as dioxane or diethyl ether.

For some anilines ( 2 ), an alternative route (Method B) can be used, where N-acylation of intermediate 4 with acroloyl chloride followed by ring-closing metathesis using Grubb's II catalyst afforded the unsaturated lactam 11. Intermediate 11 can be saturated under suitable conditions, such as hydrogenation or by conjugate reduction with nickel boride generated in situ. Removal of the piperidine nitrogen protecting group under suitable conditions, as described above, afforded intermediate 9 .

Intermediate 9 can readily react with a number of substrates to form

compounds of the present invention, such as, for example, compounds bearing a heteroaromatic ring (Scheme 2).

Scheme 2

where R ¹ and R ⁴ are as defined in formula I, embodiment 1.

Compounds of formula (I), where X1 is O and ^R2 is H, were prepared according to Schemes 3 and 4:

Scheme 3

Dihydroxylation of intermediate 4 followed by oxidative cleavage of the resulting diol using sodium periodate afforded the unstable aldehyde 13 , which was reduced to the alcohol 14 using sodium borohydride. Cyclization to intermediate 16 was accomplished in two steps using a phosgene equivalent of carbonyldiimidazole (CDI) to afford the imidazolyl carbamate 15 , followed by treatment with pyridine hydrochloride. Intermediate 17 was prepared by deprotection of the piperidine nitrogen under appropriate conditions depending on the nature of the protecting group, as described for intermediate 9 in Scheme 1.

Intermediate 17 can be readily reacted with a variety of substrates to form

compounds of the present invention, such as, for example, compounds bearing a heteroaromatic ring (Scheme 4).

Scheme 4

Compounds of formula (I), where X ¹ is CH ₂ and R ² is F, can be prepared according to Schemes 5 and 6:

Scheme 5

Copper-catalyzed conjugative borylation of unsaturated lactam 11 afforded the boronate ester 18. Oxidation of the boronate ester under suitable conditions such as sodium perborate to form the beta-hydroxy lactam, followed by removal of the protecting group for the piperidine nitrogen atom as described above, afforded intermediate 20 .

The compounds of the present invention of formula (I) can be readily formed by reaction of intermediate 20 with a variety of substrates, such as, for example, compounds bearing a heteroaromatic ring, followed by deoxyfluorination with DAST or similar reagents (Scheme 6).

Scheme 6.

In a further embodiment, a compound or salt thereof is provided selected from the group consisting of

;

,

wherein PG is a nitrogen protecting group (e.g. benzyl (Bn), carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), etc.); and PG ² is a carboxylic acid protecting group (e.g. C _1-6 alkyl or benzyl; PG ³ is carbobenzyloxy (Cbz) or tert -butoxycarbonyl (BOC); each R ^1a is halogen, each R ^1b is independently selected from F and Cl; v is 1-3, and R ¹ is phenyl optionally substituted with one, two or three halogen-containing substituents.

In another embodiment, a compound or salt thereof is provided selected from the group consisting of

where PG and PG ² are as defined above.

The compounds of this embodiment are useful in the preparation of compounds of the present invention, for example compounds of formula (I) or any of formulas (II) to (V).

The present invention further includes any variant of the processes of the present invention in which an intermediate product obtained in any step thereof is used as a starting material and the remaining steps are carried out, or in which the starting materials are obtained in situ under the reaction conditions, or in which the components of the reaction mixture are used in the form of their salts or optically pure material. The compounds of the present invention and the intermediates can also be converted into each other according to methods generally known to those skilled in the art .

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration) and rectal administration. Topical administration can also refer to inhalation or intranasal use. The pharmaceutical compositions of the present invention can be prepared in solid form (including, but not limited to, capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including, but not limited to, solutions, suspensions or emulsions). Tablets can be film-coated or enteric-coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of:

a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, such as with silicon dioxide, talc, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; also in the case of tablets

c) binders, such as with magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) leavening agents, such as with types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; and

e) absorbents, coloring agents, flavorings and sweeteners.

Method of use according to the present invention

Compounds of any of the formulae (I) to (V) in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as LTC4S modulating properties, such as demonstrated by the in vitro tests presented in the following sections, and are therefore intended for therapy or for use as research chemicals, such as pharmacologically active compounds.

The compounds of the present invention may be useful in the treatment of an indication selected from respiratory diseases/disorders, inflammation and/or diseases/disorders characterized by an inflammatory component, such as allergic disorders, asthma, wheezing in children, chronic obstructive pulmonary disease, aspirin-induced respiratory disease, bronchopulmonary dysplasia, cystic fibrosis, interstitial lung disease (e.g. sarcoidosis, pulmonary fibrosis, scleroderma lung disease, and usual interstitial pneumonia), ear, nose and throat diseases (e.g. sinusitis, rhinitis, nasal polyposis, rhinosinusitis, otitis media, and allergic eosinophilic esophagitis), eye diseases (e.g. conjunctivitis and giant papillary conjunctivitis), skin diseases (e.g. psoriasis, atopic dermatitis, eczema, and chronic urticaria), rheumatic diseases (e.g. rheumatoid arthritis, arthritis, arthrosis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, systemic sclerosis), vasculitis (eg, Henoch-Schonlein purpura, Loeffler syndrome, and Kawasaki disease), cardiovascular diseases (eg, atherosclerosis, cerebrovascular disease, acute ischemic heart disease, and treatment after myocardial infarction), gastrointestinal diseases (eg, eosinophilic gastrointestinal diseases, inflammatory bowel disease, irritable bowel syndrome, colitis, abdominal and gastric bleeding), urological diseases (eg, glomerulonephritis, interstitial cystitis, nephritis, nephropathy, nephrotic syndrome, hepatorenal syndrome, and nephrotoxicity), central nervous system diseases (eg, cerebral ischemia, spinal cord injury, migraine, multiple sclerosis, and disorders of the breathing during sleep), endocrine diseases (eg, autoimmune thyroiditis, diabetes-related inflammation), urticaria, anaphylaxis, angioedema, edema in kwashiorkor, dysmenorrhea due to burn oxidative damage, polytrauma, pain (inflammatory and neuropathic), endotoxin shock, sepsis, bacterial infections (eg, those caused by Helicobacter pylori, Pseudomonas aerugiosa, or Shigella dysenteriae), fungal infections (eg, vulvovaginal candidiasis), viral infections (eg, hepatitis, meningitis, parainfluenza, and respiratory syncytial virus), hypereosinophilic syndrome and malignancies (eg, Hodgkin's lymphoma, leukemia (eg, eosinophilic leukemia and chronic myelogenous leukemia), mastocytosis, true polycythemia and ovarian carcinoma).

Thus, as a further aspect, the present invention provides the use of a compound of formula (I) or any of formulas (II) to (V) in therapy. In a further embodiment, the therapy is selected from the therapy of a disease that can be treated by inhibiting LTC4S . In another embodiment, the disease is selected from the above list, preferably from allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably from asthma, atopic dermatitis or chronic urticaria.

Thus, as a further aspect, the present invention provides a compound of any of formulas (I) to (V) for use in therapy. In a further embodiment, the therapy is selected from the therapy of a disease that can be treated by inhibiting LTC4S . In another embodiment, the disease is selected from the above list, preferably from allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably from asthma, atopic dermatitis or chronic urticaria.

In another aspect, the present invention provides a method for treating a disease, the treatment of which is carried out by LTC4S inhibition, comprising administering a therapeutically effective amount of a compound of any of formulas (I)-(V). In a further embodiment, the disease is selected from the above list, preferably from allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably from asthma, atopic dermatitis or chronic urticaria.

Thus, as a further aspect, the present invention provides the use of a compound of any of the formulae (I) to (V) for the manufacture of a medicament. In a further embodiment, the medicament is for the treatment of a disease, the treatment of which can be achieved by inhibiting LTC4S . In another embodiment, the disease is selected from the above list, preferably from allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably from asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention there is provided 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one for use in the treatment of a disease selected from the above list, preferably for the treatment of allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention there is provided (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one for use in the treatment of a disease selected from the above list, preferably for the treatment of allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention there is provided (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one for use in the treatment of a disease selected from the above list, preferably for the treatment of allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably for the treatment of asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention, there is provided 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one for use in the treatment of a disease selected from the above list, or for the treatment of allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably for the treatment of asthma, atopic dermatitis or chronic urticaria.

In another embodiment of the present invention there is provided 9-(2-amino-6-(4-(trifluoromethyl)-1H - pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one for use in the treatment of a disease selected from the above list, preferably allergic disorders, asthma, aspirin-induced respiratory disease (AERD), COPD, cystic fibrosis, dermatitis, urticaria, rhinitis (allergic rhinitis), nasal polyposis, rhinosinusitis, conjunctivitis, eosinophilic gastrointestinal diseases and inflammatory bowel disease, and more preferably for the treatment of asthma, atopic dermatitis or chronic urticaria.

The pharmaceutical composition or combination of the present invention can be presented in a single dosage of about 1-1000 mg of the active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredients. The therapeutically effective dosage of the compound, pharmaceutical composition or combinations thereof depends on the type of subject, body weight, age and the individual condition, disorder or disease being treated or its severity. An attending physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progression of a disorder or disease.

The above mentioned dosage parameters are evident in the tests.in vitroAnd in vivousing mainly mammals, such as mice, rats, dogs, non-human primates, or isolated organs, tissues and preparations thereof. The compounds of the present invention can be usedin vitroin the form of solutions, for example, aqueous solutions, andin vivoenterally or parenterally, preferably intravenously, for example, in the form of a suspension or aqueous solution. Dosagein vitrocan be in the concentration range of approximately 10^-3mol/l up to 10^-9mol/l. Depending on the route of administration, the therapeutically effective amountin vivomay range from approximately 0.1-500 mg/kg or from approximately 1-100 mg/kg.

The combination product and combination therapy of the present invention.

"Combination" refers to a fixed combination in a single dosage unit or to combined administration, wherein a compound of the present invention and a combination partner (e.g., another drug, as explained below, also referred to as a "therapeutic agent" or "co-administered agent") may be administered independently at the same time or separately at intervals, especially where the intervals allow the combination partners to exert a cooperative, e.g., synergistic, effect. The individual components may be packaged in a kit or provided separately. One or both components (e.g., powders or liquids) may be reconstituted or diluted to the desired dose prior to administration. The terms "co-administration" or "combination administration" or the like, as used herein, are intended to encompass the administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one therapeutic agent, which includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that both therapeutic agents, for example, a compound of the present invention and a combination partner, are administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" means that both therapeutic agents, for example, a compound of the present invention and a combination partner, are administered to a patient as separate entities simultaneously, in parallel or sequentially without specific time limits, whereby such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter is also applicable to "cocktail therapy", for example, when administering three or more therapeutic agents.

As used herein, the term "pharmaceutical combination" refers to a fixed combination in a single dosage unit or a non-fixed combination or kit of parts for combined administration, wherein two or more therapeutic agents can be administered independently at the same time or separately at intervals, especially where such intervals allow the combination partners to exhibit a cooperative, e.g., synergistic, effect.

The term "combination therapy" refers to the administration of two or more therapeutic agents for the treatment of a therapeutic condition or disorder described herein. Such administration encompasses co-administration of the therapeutic agents substantially simultaneously, such as in a single capsule having a fixed ratio of the active ingredients. Alternatively, such administration encompasses co-administration in multiple or separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the required dose prior to administration. In addition, such administration also encompasses the use of each type of therapeutic agent sequentially, either at approximately the same time or at different times. In either case, the treatment regimen will provide the beneficial effects of the combination of drugs in the treatment of the conditions or disorders described herein.

The compound of the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compound of the present invention can be administered separately from the other agents by the same or a different route of administration, or together with them in a single pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compound of the present invention.

In one embodiment, the present invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combination preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by LTC4S. Products provided as a combination preparation include a composition comprising a compound of any of formulas (I) to (V) and the other therapeutic agent(s) together in the same pharmaceutical composition, or a compound of any of formulas (I) to (V) and the other therapeutic agent(s) in separate form, such as in the form of a set.

In one embodiment, the present invention provides a pharmaceutical combination comprising a compound of any of formulas (I)-(V) and another therapeutic agent(s). The pharmaceutical combination may optionally comprise a pharmaceutically acceptable carrier as described above.

In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of any of formulae (I)-(V). In one embodiment, the kit comprises means for separately containing said compositions, such as a container, a compartmental bottle, or a compartmental foil pouch. An example of such a kit is a blister pack, typically used for packaging tablets, capsules, etc.

The kit of the present invention can be used to administer different dosage forms, such as oral and parenteral administration, to administer separate compositions at different dosing intervals, or to titrate separate compositions relative to each other. To promote compliance, the kit of the present invention typically includes instructions for administration.

In the combination therapies of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy: (i) prior to dispensing the combination product to physicians (e.g., in the case of a kit containing a compound of the present invention and another therapeutic agent); (ii) by the physicians themselves (or under the guidance of a physician) shortly before administration; (iii) by the patients themselves, for example, during sequential administration of a compound of the present invention and another therapeutic agent.

Accordingly, the present invention provides the use of a compound of any of formulas (I)-(V) for the treatment of a disease or condition mediated by LTC4S, wherein the drug is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by LTC4S, wherein the drug is administered with a compound of any of formulas (I)-(V).

The present invention also provides a compound of any of formulas (I)-(V) for use in a method of treating a disease or condition mediated by LTC4S, wherein the compound of formula (I), (II), (III), (IV), or (V) is formulated for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by LTC4S, wherein the other therapeutic agent is formulated for administration with a compound of formula (I), (II), (III), (IV), or (V). The present invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by LTC4S, wherein the compound of formula (I), (II), (III), (IV), or (V) is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by LTC4S, wherein the other therapeutic agent is administered with a compound of formula (I), (II), (III), (IV) or (V).

The present invention also provides the use of a compound of any of formulas (I)-(V) for the treatment of a disease or condition mediated by LTC4S, wherein the patient has previously (e.g., within 24 hours) has been treated with another therapeutic agent. The present invention also provides for the use of another therapeutic agent in the treatment of a disease or condition mediated by LTC4S, wherein the patient has previously (e.g., within 24 hours) was treated with a compound of formula (I), (II), (III), (IV) or (V).

In one embodiment, the other therapeutic agent is a therapeutic agent useful in the treatment of a respiratory disease and/or a therapeutic agent useful in the treatment of inflammation and disorders with an inflammatory component (anti-inflammatory drugs).

In one embodiment, the other therapeutic agent useful in the combination therapy is selected from a steroid; corticosteroids; glucocorticosteroids; non-steroidal glucocorticoid receptor agonists; leukotriene receptor antagonists (LTRA), including LTB4 antagonists, LTD4 antagonists, leukotriene A4 hydrolase inhibitors (LTA4H), cysteinyl leukotriene receptor antagonists (including montelukast, pranlukast, zafirlukast); a prostaglandin pathway modulator (e.g., a CRTH2/DP2 receptor antagonist); Bruton tyrosine kinase inhibitors (BTK inhibitors); PDE4 inhibitors; antihistamines; histamine H4 receptor antagonists; H1 receptor antagonists; beta-adrenergic drugs such as beta-(β)-2-adrenergic receptor agonists; anticholinergic drugs or both anticholinergic and antimuscarinic drugs (e.g. M2 and/or M3 antagonists); non-steroidal anti-inflammatory drugs ("NSAIDs"); analgesics; 5-lipoxygenase inhibitors; FLAP (5-lipoxygenase activating protein) inhibitors; selective COX-2 inhibitors; and statins.

Suitable steroids include, in particular, glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, fluticasone furoate, ciclesonide or mometasone furoate; or non-steroidal glucocorticoid receptor agonists such as velsecorate (AZD7594)

Suitable PDE4 inhibitors include, for example, roflumilast, aprelimast, crisaborole, lotamilast, ensifentrine (RPL554) and CHF 6001.

Suitable beta (β)-2-adrenergic receptor agonists are, for example, albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol and especially formoterol and their pharmaceutically acceptable salts, and the compounds (in free form or in the form of a salt or solvate) of formula (I) in WO 00/75114, which document is incorporated herein by reference, preferably the compounds of the examples thereof, especially the compound of formula

and pharmaceutically acceptable salts thereof, as well as the compounds (in free form or in the form of a salt or solvate) of formula (I) in WO 04/16601. Further β-2-adrenergic receptor agonists include vilanterol, olodaterol and abediterol.

Suitable bronchodilator drugs include anticholinergic or antimuscarinic agents, particularly ipratropium bromide, oxitropium bromide, tiotropium salts, glycopyrromide bromide, umeclidinium bromide and aclidinium bromide.

Suitable antihistamine (H1 antagonist) substances that are drugs include cetirizine hydrochloride, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride.

Suitable β ₂ -agonists for use in the present invention include, but are not limited to, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterol, nolomirole, orciprenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, salmefamol, salmeterol, sibenadet, soterot, sulfonterol, terbutaline, tiaramide, tulobuterol, carmoterol, QAB-149 (also known as indacaterol), olodaterol, abediterol, and vilanterol, and l and combinations thereof, each of which optionally present in the form of a racemate, enantiomer, diastereomer or mixtures thereof, and optionally in the form of a pharmacologically compatible acid addition salt.

Suitable corticosteroids and glucocorticoids for use in the present invention include, but are not limited to, prednisolone, methylprednisolone, dexamethasone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredane, hydrocortisone aceponate, prednicarbate, alclomethasone dipropionate, halomethasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesilate, ciclesonide, deprodone propionate, fluticasone propionate, fluticasone furoate, halobetasol propionate, loteprednol etabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone 17-valerate, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate, prednisolone phosphate sodium, hydrocortisone probutate and their combinations.

Suitable LTD4 antagonists for use in the present invention include, but are not limited to, tomelukast, ibudilast, pobilukast, pranlukast hydrate, zafirlukast, ritolukast, verlukast, sulukast, cinalukast, iralukast sodium, montelukast sodium, 4-[4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutyric acid, [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid, 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(lH-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one, sodium salt of 5-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-8-(N,N-dimethylcarbamoyl)-4,6-dithiaoctanoic acid; sodium salt of 3-[1-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxopropylsulfanyl]methylsulfanyl]propionic acid, 6-(2-cyclohexylethyl)-[1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(lH-one, 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid, (R)-3-methoxy-4-[1-methyl-5-[N-(2-methyl-4,4,4-trifluorobutyl)carbamoyl]indol-3-ylmethyl]-N-(2-methylphenylsulfonyl)benzamide, (R)-3-[2-methoxy-4-[N-(2-methylphenylsulfonyl)carbamoyl]benzyl]-1-methyl-N-(4,4,4-trifluoro-2-methylbutyl)indole-5-carboxamide, (+)-4(S)-(4-carboxyphenylthio)-7-[4-(4-phenoxybutoxy)phenyl]-5(Z)-heptenoic acid, the compounds of International Application No. PCT/EP03/12581 and combinations thereof.

Suitable NSAIDs for use in the present invention include, but are not limited to, aceclofenac, acemetacin, acetylsalicylic acid, alclofenac, alminoprofen, amfenac, ampiroxicam, amtolmetin guacil, anirolac, antrafenine, azapropazone, benorilate, bermoprofen, bindarit, bromfenac, bucloxic acid, bucolom, bufexamac, bumadizone, butibufen, butixirate, calcium carbasalate, carprofen, choline magnesium trisalicylate, celecoxib, cinmetacin, cinnoxicam, clidanac, clobuzarit, deboxamet, dexibuprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, enfenaminsaur, ethersalate, etodolac, etofenamate, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, fenoprofen, fentiazac, fepradinol, feprazone, flobufen, floctafenine, flufenamic acid, flufenisal, flunoxaprofen, flurbiprofen, flurbiprofenaxetil, furofenac, furprofen, glucametacin, ibufenac, ibuprofen, indobufen, indomethacin, indomethacin farnesyl, indoprofen, isoxepac, isoxicam, ketoprofen, ketorolac, lobenzarit, lonazolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, meclofen, mefenamic acid, meloxicam, mesalazine, miroprofen, mofezolac, nabumetone, naproxen, niflumic acid, olsalazine, oxaprozin, oxypinac, oxyphenbutazone, parecoxib, phenylbutazone, pelubiprofen, pimeprofen, pyrazolac, piroxicam, pirprofen, pranoprofen, prifelon, prinomod, proglumetacin, proquazone, protizininzaur, rofecoxib, romazarit, salicylamide, salicylic acid, salmistein, salnacedin, salsalate, sulindac, sudoxicam, suprofen, talniflumate, tenidap, tenosal, tenoxicam, tepoxalin, tiaprofenic acid, taramide, tilnoprofen arbamel, thymegadine, tinoridine, thiopenac, tolfenamic acid, tolmetin, ufenamate, valdecoxib, ximoprofen, zaltoprofen, zoliprofen and their combinations.

Suitable leukotriene A4 hydrolase inhibitors include the compounds described in WO2015/092740, WO2014/164658, WO2014/152536, WO2014/152518, WO2014/152229, WO2012/125598, WO2013/012844, WO2014/014874, WO2013/134226, WO2015/009609, WO2015/009611, WO2013/131901.

Of particular interest is the compound described in WO2015/092740; for example a compound selected from ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof).

Other LTA4H inhibitors of particular interest include acebilustat, CTX-3397, or the compound described in WO2014/164658 and more particularly the compound 4-((( 1S , 4S )-5-(4-(4-(oxazol-2-yl)phenoxy)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)benzoic acid:

or its pharmaceutically acceptable salt.

Suitable H4-histamine receptor antagonists include, for example, the compound described in US 7,943,628, and preferably the compound of Example 9, which is N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine:

or a pharmaceutically acceptable salt thereof, preferably its L-titrate salt.

Suitable BTK inhibitors include, for example, ibrutinib, acalabrutinib (ACP-196), evobrutinib; fenebrutinib; tirabrutinib (ONO-4059, GS-4059); zanubrutinib (BGB-3111), spebrutinib (CC-292, AVL-292), poseltinib (HM-71224, LY3337641), vecabrutinib (SNS-062), BMS-986142; BMS986195; PRN2246; PRN1008, M7583, CT1530, BIIBO68, AC-0058TA, ARQ-531, TAK-020, TG1701 or a compound described in WO2015/079417, WO2015/083008, WO2015/110923, WO2014/173289, WO2012/021444, WO2013/081016, WO2013/067274, WO2012/170976, WO2011/162515, US2017/119766, WO2016/065226, US9688676, WO2016/201280, WO2017/059702, US9630968, US2014/0256734, WO2017118277, WO2014/039899, WO/16/105531, WO2018/005849, WO2013/185082 or in the Journal of Medicinal Chemistry, 2016 59 (19) 9173-9200.

Of particular interest are BTK inhibitors including the compound of Example 31 described in WO2014/039899, wherein the compound is characterized by the following structure:

and is described as compound 14f in Journal of Medicinal Chemistry, 2016, 59(19), 9173-9200; the compound of example 2 described in US2017/119766, the compound of example 223 described in WO2016/065226, which is

or compound 1 described in WO2016/201280, compound 1 described in WO2017/059702 or compound 1 described in WO2017/118277, or a pharmaceutically acceptable salt thereof.

Also of particular interest are BTK inhibitors comprising a compound as described in WO2015/079417, for example a compound selected from N- (3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.

Suitable CRTH2/DP2 receptor antagonists include fevipiprant, timapiprant, or [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-ethylquinolin-5-yloxy]acetic acid L-lysine salt (GB001)

or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the second therapeutic agent is selected from

1. a prostaglandin pathway modulator (eg, a CRTH2/DP2 receptor antagonist, eg, fevipiprant);

2. a leukotriene A4 hydrolase inhibitor (more particularly a compound described in WO 2015/092740; preferably a compound selected from ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2 H -tetrazol-2-yl)butanoic acid; or a pharmaceutically acceptable salt thereof);

3. an H4-histamine receptor antagonist (e.g. the compound described in US Patent 7,943,628, and preferably the compound of Example 9, which is N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine:

or a pharmaceutically acceptable salt thereof, preferably its L-titrate salt; and

4. a BTK inhibitor (e.g. a compound described in WO2015/079417, and preferably a compound selected from N- (3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention there is provided a product comprising 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from fevipiprant, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamine, N -(3-(5-((1-acryloyl azetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, as a combination drug for simultaneous, separate or sequential use in therapy.

In one embodiment of the present invention there is provided a product comprising 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof and a second therapeutic agent selected from fevipiprant, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl) -2H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamine, N -(3-(5-((1-acryloyl azetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, as a combination drug for simultaneous, separate or sequential use in therapy.

In one embodiment of the present invention there is provided a product comprising 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof and a second therapeutic agent selected from fevipiprant, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamine, N -(3-(5-((1-acryloyl azetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, as a combination drug for simultaneous, separate or sequential use in therapy.

In one embodiment of the present invention there is provided a product comprising 9-(2-amino-6-(4-(trifluoromethyl)-1H - pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof and a second therapeutic agent selected from fevipiprant, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamine, N -(3-(5-((1-acryloyl azetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N -(3-(6-amino-5-(2-( N -(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, as a combination drug for simultaneous, separate or sequential use in therapy.

In one embodiment of the present invention, there is provided a product comprising (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent selected from fevipiprant, ( S )-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(3-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( S )-3-amino-4-(5-(4-( p -tolyloxy)phenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-butoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-phenethoxyphenyl)-2 H -tetrazol-2-yl)butanoic acid; ( R )-3-amino-4-(5-(4-(4-chlorophenoxy)phenyl)-2H - tetrazol-2-yl)butanoic acid; N ⁴ -(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine, N -(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-((1-propioloylazetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N- (3-(6-amino-5-(2-( N- (2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; ( S )- N- (3-(6-amino-5-(2-( N -methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N- (3-(6-amino-5-(3-( N- methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof, as a combination drug for simultaneous, separate or sequential use in therapy.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from fevipiprant, (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from fevipiprant, (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention there is provided a pharmaceutical composition comprising (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one, or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from fevipiprant, (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from fevipiprant, (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, there is provided a pharmaceutical composition comprising 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from fevipiprant, (S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid; (R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid; N⁴-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidine-2,4-diamine,N-(3-(5-((1-acryloylazetidin-3-yl)oxy)-6-aminopyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-((1-propioloyl azetidin-3-yl)oxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylpropiolamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-ethylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide;N-(3-(6-amino-5-(2-(N-(2-fluoroethyl)acrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(but-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; (S)-N-(3-(6-amino-5-(2-(N-methylbut-2-ynamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide and N-(3-(6-amino-5-(3-(N-methylacrylamido)propoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

BIOLOGICAL ANALYSES AND DATA

The activity of the compound according to the present invention can be assessed by the following methodsin vitro. The compound of formula (I) or a pharmaceutically acceptable salt thereof exhibits valuable pharmacological properties, such as properties of susceptibility to LTC4S, such as those shown in the tests presented in the following sections, and are therefore indicated for LTC4S-related therapy.

A. Enzymatic analysis of human LTC4S

LTC synthase₄catalyzes the conversion of leukotriene A₄(LTA₄) into leukotriene C₄(LTC₄) in the presence of reduced glutathione (GSH) as a substrate cofactor. For compound testing, compounds were supplied as 10 mM stock solutions in 90% DMSO in Matrix tubes. From this, dose-dependent 1:3 dilution series were prepared with initial concentrations ranging from 30 μM to 0.1 nM. For the enzymatic assay, 97.5 nL of the compound/DMSO solution is added to each well and 5 µL of the enzyme solution is added to the wells (assay buffer: 50 mM bis-tris-propane, pH = 7.3, 250 mM NaCl, 10 mM MgCl₂, 0.001% MGN3). The final enzyme concentration in the assay is 0.75 nM. The enzyme compound mixture is incubated at room temperature for 15 minutes before adding 5 µl of substrate solution. Since the primary substrate LTA₄is a highly unstable intermediate in the arachidonic acid pathway, for LTA screening purposes₄are replaced by a more stable form of the methyl ester LTA₄(LTA₄-Me). The final concentration of GSH substrate is selected to be 400 μM and LTA₄-Me, which is 5 μM.

LTA ₄ -Me is commercially available in 2% triethylamine/hexane solvent. Since this solvent is incompatible with the HTRF assay, it was replaced with DMSO according to the following procedure: add 50 µL of 100% DMSO to 50 µL of LTA ₄ -Me (3 mM) in a 2 mL Eppendorf tube and mix gently by inverting the tube. The triethylamine/hexane mixture was evaporated under a constant flow of argon at room temperature. Aliquot DMSO-LTA ₄ -Me (3 mM) and store at -20 °C for up to 4 weeks, since it is unstable in DMSO due to its oxidative properties.

After addition of the substrate, the plate is immediately placed on a shaker for 5 min at room temperature. Immediately after 5 min of incubation, 5 µl of H ₂ O ₂ solution is added to all wells to stop the reaction. The plate contents are mixed before adding the detection reagents. The conversion from LTA ₄ -Me and GSH to LTC ₄ -Me is quantified using an LTC ₄ -Me standard curve ranging from 1.5 µM to 0.08 nM. For detection of the LTC ₄ -Me enzymatic reaction product, the Cisbio LTC ₄ -HTRF kit is used since the assay is compatible with LTC ₄ -Me detection. To all wells of the assay plate, 5 µl of diluted LTC ₄ -d2 conjugate (according to the manufacturer's protocol) are added and the contents are gently mixed and incubated for 5 min at room temperature. Then 5 μl of diluted LTC ₄ -Eu3+ cryptate (according to the manufacturer's protocol) are added to all wells and the plate contents are gently mixed and incubated for 60 min at room temperature before reading the plate on a Spectramax Paradigm (Molecular Devices) using a ratiometric assay (665/616 nM) and the following initial settings: number of flashes/well is 30, integration time is 0.3 ms, excitation time is 0.05 ms, positioning delay is 0.03 ms and multiplier gain is 10000. The percentage inhibition for each point on the inhibition curve is calculated after interpolating the data using the LTC ₄ -Me standard curve to convert the HTRF signal into the amount of LTC ₄ -Me produced in the LTC ₄ S-catalyzed reaction in each plate. The data are analyzed using parametric curve fitting to determine IC ₅₀ values for LTC ₄ S inhibitors. Due to the assay setup, the maximum detectable potency of the compounds is approximately 2-4 nM. Therefore, compounds with potency that could theoretically result in IC ₅₀ values below 2 nM are measured in dilute stock solutions, typically with a starting concentration of 1 µM in the assay.

B. HTRF analysis of human whole blood

LTC ₄ synthase catalyzes the conversion of leukotriene A ₄ (LTA ₄ ) to leukotriene C ₄ (LTC ₄ ) in the presence of reduced glutathione (GSH) as a substrate cofactor. For LTC ₄ S inhibition testing, compounds were prepared for either eight-point or sixteen-point dose-response studies in Labcyte 384-well low dead volume (LDV) plates. For eight-point dose-response studies, compounds were diluted 1:5 starting at 1 μM in 90% DMSO. For sixteen-point dose-response studies, compounds were diluted 1:3,333 starting at 10 μM in 90% DMSO. Compounds were tested in duplicate. Ten wells were filled with 90% DMSO, corresponding to stimulated and unstimulated control wells. The day before the assay, 100 nL from each well, i.e., each compound at each concentration, was printed from a Labcyte LDV plate into each corresponding well of an assay plate (Greiner BioOne #784201) using a Labcyte Echo 650 Acoustic Fluidic Handler and stored at 4°C. Whole blood was collected from three human donors on the morning of the assay. Donors were required to be nonsmokers and have not taken an NSAID within 48 hours prior to blood collection. The amount of blood collected from a single donor depends on the number of compounds to be tested and the dose-response format in which they are to be studied (approximately 8 mL of whole blood for either 22 compounds in an 8-point dose-response format or 11 compounds in a 16-point dose-response format). Whole blood from three donors is diluted 1:3 in RPMI 1640 medium (Gibco #72400-047). 50 µL of the diluted blood pre-spiked with compounds and DMSO for stimulated and unstimulated controls are then added to each well of the assay plate using a Thermo Scientific™ Multidrop™ Combi reagent dispenser and incubated at 37°C for 4 hours. Calcium ionophore A23187 is used to induce a rapid increase in intracellular Ca ²⁺ levels. Ca ²⁺ functions as a universal second messenger in a variety of immune cells such as T cells, B cells, and mast cells and is used to induce degranulation and release of eicosanoids, including LTC ₄ , by cells contained in whole blood samples. Shortly before the end of the 4-hour incubation, 0.5 mg/mL calcium ionophore A23187 was prepared by mixing (per mL) 20 μL of a 25 mg/mL calcium ionophore A23187 stock solution (Sigma-Aldrich, #C-7522) in 950 μL of prewarmed (37°C) RPMI 1640 medium and 30 μL of dimethyl sulfoxide (DMSO). All wells except the unstimulated controls were subsequently stimulated by adding 1 μl of a 0.5 mg/ml calcium ionophore suspension using a Thermo Scientific™ Multidrop™ Combi reagent dispenser. The plates were incubated for 15 min at 37°C. The plates were then centrifuged at 300 g for 10 min at room temperature to pellet the blood cells and stop the reaction. Finally, 25 μl of the resulting supernatants were removed from each well using a Beckman Coulter Biomek FX ^P automated liquid handler into empty 384-well plates (Greiner BioOne #781281) for storage. The plates were sealed and stored at -80°C.

To measure the amount of LTC ₄ released by cells in human blood samples during calcium ionophore stimulation, supernatants were analyzed using the Cisbio LTC ₄ Homogeneous Time-Resolved FRET (HTRF) Assay (Cisbio #64LC4PEH). Human whole blood supernatants were thawed and diluted by transferring 3.5 µL from each well to white high-base, low-volume plates (Greiner BioOne #784075) already containing 6.5 µL of Diluent #3 (Cisbio #62DL3DDD). Ten serial dilutions of the calibration curve were also added to each plate in duplicate as specified in the protocol. Blank and cryptate control wells were also prepared. Then, 5 µl of anti-LTC ₄ -d2 working solution is added to all wells except the control wells with cryptate. Then, 5 µl of anti-LTC ₄ -Eu3+ cryptate working solution is added sequentially to all wells. The plates are then covered with a lid and incubated at room temperature for one hour with gentle orbital shaking (~450 rpm). Time-resolved fluorescence at 665 and 620 nm is measured after incubation using a BMG LABTECH CLARIOstar® (50 flashes/well, integration starts at 60 µs for 400 µs, focal height 12.0 mm). HTRF ratios were calculated for each well by dividing the intensity at 665 nm by the intensity at 620 nm and multiplying the resulting ratio by 10,000. LTC ₄ standard curves were interpolated for each plate and used to convert HTRF ratio readings to the amount of LTC ₄ present in each well (in ng/mL). Parametric curve fitting was used to generate inhibition curves and IC ₅₀ values.

Table 1

Example No. IC ₅₀ Human LTC4S
(enzymatic analysis) IC ₅₀ HTRF of human whole blood 1 6 13 2 36 - 3 8 180 4 7 50 5 5 10 6a 190 310 6b 44 - 7 76 100 8 7 - 9 2 48 10 - 5 11 - 6 12 - 2 13 - 36 14 - 1 15a - 1 15b - 180 16 - 16 17 - 9 18 - 2 19 - 3 20 12 64 21 4 7 22 11 530 23 61 45 24 33 110 25 62 170 26 16 110 27 25 59 28 110 450 29 57 180 30 13 360 31 15 120 32 7 170 33 24 56 34 - 2 35a 12 40 35b 3 - 36 6 44 37 12 120 38 8 86 39 - 4 40 - 4 41 - 5 42 - 410 43 - 400 44 13 - 45 - 620 46 - 490 47 - 7 48 - 45 49 - 88 50 - 45 51 - 70 52 - 29 53 - 1140 54 - 300 55 - 6 56 - 17 57 - 850 58 - 560 59 - 640 60 - 680 61 - 29 62 - 410 63 - 430 64 - 2 65 - 1 66 - 1 67, racemic - 2 68 - 120 69 - 35 70 - 110 71 - 580 72 - 760 73 - 68 74 - 4 75 - 4 76 - 57 77 - 31 78 - 24 79 - 56 80 - 24 81 13 72 82 12 21 83 9 9 84 8 9 85 - 430 86, racemic - 2 87 - 7 88 - 1370 89a - 1 89b - 5 90 - 4 91 - 3 92 - 5 93 - 10 94 - 830 95, racemic - 2 96, racemic - 3 97 - 3 98 - 3 99 - 4 100 - 2 101 - 5 102, racemic - 9 103 - 8 104, racemic - 5 105, racemic - 6 106 - 69 107 - 6 108, racemic - 22 109 - 15 110a - 3 110b - 5 111, racemic - 17 112 - 67 113a - 15 113b - 36 114 - 7 115 - 28 116a - 13 116b - 33 117 - 18 118 - 8 119 - 29 120 - 32

EXPLANATION OF THE INVENTION WITH EXAMPLES

The present invention is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and that this does not impose any limitations on the scope of the present invention. In addition, it should be understood that various other embodiments, modifications and equivalents can be resorted to, which can 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.

The compounds of the present invention can be prepared by methods known in the art of organic synthesis. It is understood that in all methods, protective groups for unstable or reactive groups can be used, if desired, in accordance with the general principles of chemistry. The handling of protective groups is carried out in accordance with standard methods of organic synthesis (TW Green and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a suitable stage in the synthesis of the compound using methods obvious to those skilled in the art.

Unless otherwise stated, reagents and solvents were used as obtained from private suppliers. Proton nuclear magnetic resonance (NMR) spectra are reported in ppm (δ) and coupling constants, J , are given in hertz. Tetramethylsilane ( TMS ) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or another solvent as specified in the NMR data. A small amount of dry sample (2–5 mg) was dissolved in a suitable deuterated solvent (1 ml). Chemical names were generated using ChemBioDraw Ultra v12 from CambridgeSoft.

Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were carried out under reduced pressure, typically from about 15 mmHg to 100 mmHg (= 20-133 mbar). The structure of the final products, intermediates and starting materials was confirmed by standard analytical methods, e.g. microanalysis and determination of spectroscopic characteristics, for example, by MS, IR, NMR. The abbreviations used are standard abbreviations used in the given technical field.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be prepared by organic synthetic methods known to those of ordinary skill in the art.

Abbreviations used in the following examples and other sections:

2-MeTHF 2-methyltetrahydrofuran

ACN acetonitrile

AcOH acetic acid

Bn or Bzl benzyl

Boc tert -butyloxycarbonyl

Boc ₂ O di-tert-butyl dicarbonate

B ₂ Pin ₂ 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane, bis(pinacolato)diboron

br wide

saline solution saturated aqueous solution of NaCl

cHex cyclohexane

d doublet

DAST (diethylamino)sulfur trifluoride

DBU 1,8-diazabicyclo(5.4.0)undec-7-ene

DCE dichloroethane

DCM dichloromethane

dd doublet of doublets

DIAD diisopropyl azodicarboxylate

DIBAH diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAP dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

DPEPhos bis[(2-diphenylphosphino)phenyl] ether

EDC.HCl N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

Et ₂ O diethyl ether

EtOAc ethyl acetate

EtOH ethanol

eq equivalent(s)

equiv. equivalent(s)

Ex example(s)

h hour

HCI hydrochloric acid

HOBt 1-hydroxybenzotriazole

HPLC high performance liquid chromatography

IPA isopropanol

LC liquid chromatography

LiHMDS lithium bis(trimethylsilyl)amide

m multiplet/milli, depending on context

mCPBA 3-chloroperoxybenzoic acid

MeCN acetonitrile

MeOH methanol

mg milligram

min. minutes

MS mass spectrometry

ml milliliter

mmol millimole

MTBE methyl tert-butyl ether

mass/charge mass to charge ratio

NMR nuclear magnetic resonance

ppm parts per million

PyBrop Bromo-tris-pyrrolidinophosphonium hexafluorophosphate

q quartet

quint quintet

k.t. room temperature

RP reversed phase

s singlet

SFC supercritical fluid chromatography

t triplet

TBME tert -butyl methyl ether

t Bu tert -butyl

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

™ SCN trimethylsilyl cyanide

t _R retention time

UPLC Ultra Performance Liquid Chromatography

Analysis details

NMR. Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ 600 (600 MHz), Agilent VNMRS-300 (300 MHz) spectrometer with or without trimethylsilane as an internal standard. Chemical shifts (δ-values) are given in ppm, counted from tetramethylsilane, with the spectra in the splitting scheme designated as singlet ( s ), doublet ( d ), triplet ( t ), quartet ( q ), quintet ( quint ), multiplet, unresolved or overlapping signals ( m ), broad signal ( br ). Deuterated solvents are given in brackets.

LC-MS:

LCMS method a:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity HSS T3, 2.1 x 50 mm, 1.8 µm; column temperature: 60°C.

Gradient: 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mM ammonium acetate, B=acetonitrile+0.04% formic acid, flow rate: 1.0 ml/min.

LCMS method b:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity CSH C18, 2.1 x 50 mm, 1.7 µm; column temperature: 50°C.

Gradient: 5 to 98% B in 1.8 min, A=water+0.1% _NH3 , B=acetonitrile+0.1% _NH3 , flow rate: 1.0 ml/min.

LCMS method c:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1 × 50 mm; column temperature: 50°C.

Gradient: 3 to 98% B in 4.8 min, A=water+0.05% formic acid, B=acetonitrile+0.05% formic acid, flow rate: 0.6 ml/min.

LCMS method d:

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1 x 50 mm, 1.7 µm; column temperature: 40°C.

Gradient: 3 to 98% B in 2.8 min, A=water+0.1% formic acid, B=acetonitrile+0.1% formic acid, flow rate: 0.8 ml/min.

LCMS method e :

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1 x 30 mm, 1.7 µm; column temperature: 40°C.

Gradient: 3 to 98% B in 2.8 min, A=water+0.1% formic acid, B=acetonitrile+0.1% formic acid, flow rate: 1 ml/min.

LCMS method f :

System: Agilent LC/MSD

Column: Zorbax C18, 4.6 x 150 mm, 5 µm; column temperature: 40°C.

Gradient: 30% to 70% B in 1 min, 70% to 100% B in 5 min; A=water+0.1% TFA, B=acetonitrile; flow rate: 1.0 ml/min.

LCMS method g :

System: Agilent LC/MSD

Column: Kinetex C18 4.6 × 100 mm, 5 µm; column temperature: 40°C.

Gradient: 0-20% B in 2 min, 20-70% B in 8 min, 70-100% B in 3 min; A=water, B=acetonitrile; flow rate: 0.75 ml/min.

LCMS method h :

System: Waters Acquity UPLC with Waters SQ detector.

Column: Acquity BEH C18, 2.1 x 30 mm, 1.7 µm; column temperature: 40°C.

Gradient: 2 to 98% B in 1.5 min, A=water+5 mM ammonium hydroxide, B=acetonitrile+5 mM ammonium hydroxide, flow rate: 1.0 ml/min.

LCMS method i :

System: Waters Acquity UPLC with Waters SQ detector

Column: Acquity BEH C18, 2.1 x 30 mm, 1.7 µm

Mobile phases, gradient: A=water +0.05% formic acid, B=methanol +0.04% formic acid; time (min)/% B: 0.0/2, 0.10/2, 0.50/80, 0.60/95, 0.80/95, 0.90/2, 1.15/2

Flow rate: 1.0 ml/min.

LCMS method j :

System: Shimadzu LCMS 2020

Column: Synergi max-RP 100Å Mercury, 4.0 × 30 mm, 2.5 µm; column temperature: 40°C

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time (min)/% B: 0/5, 0.1/5, 0.5/5, 1.0/95, 1.5/95, 2.0/5, 3.0/5

Flow rate: 2.0 ml/min.

Detection: PDA, 210 nm

LCMS method k :

System: Agilent LC/MSD

Column: Kinetex EVO, 4.6 x 50 mm, 2.6 µm; column temperature: 40°C

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time (min)/% B: 0.0/20, 0.25/20, 01.0/95.0, 2.5/95, 3.0/20, 4/20

Flow rate: 1.5 ml/min.

Detection: PDA, 210 nm

LCMS method l :

System: Sciex API-2000

Column: Synergi max-RP 100Å Mercury, 4.0 × 30 mm, 2.5 µm; column temperature: 30°C

Mobile phases, gradient: A=0.1% HCOOH in water, B=acetonitrile; time (min)/% B: 0/30, 0.5/30, 1.5/95, 2.4/95, 2.5/30, 3.0/30

Flow rate: 2.0 ml/min.

Detected by: TWC PDA

LCMS method m:

System: Agilent 1200-6120

Column: Poroshell 120 EC-C18, 4.6 × 50 mm, 2.7 µm; column temperature: 40°C

Mobile phases, gradient: A=0.1% formic acid in water, B=0.1% formic acid in acetonitrile; time (min)/% B: 0/5, 4.0/95, 6.0/95

Flow rate: 1.2 ml/min.

Detection: PDA, 210 nm

Preparative methods.

Flash chromatography system.

System: Teledyne ISCO, CombiFlash Rf.

Column: Pre-packaged RediSep Rf cartridges.

SFC:

System: Waters Preparative SFC-100-MS System:

Detection: Waters 2998 Photodiode Array Detector

Waters Single Quadrupole MS Detector

Modifier: Methanol

ABPR: 120 bar

Column temperature: 40°C

Flow rate: 100 g/min.

Preparative HPLC (RP).

System: Waters AutoPurification-MS System

Detection: Waters 2998 Photodiode Array Detector

Waters Single Quadrupole MS Detector

Column temperature: r.t.

Eluent A: water

Eluent B: acetonitrile, both containing 0.1% TFA or 0.1% NH ₄ OH

All reagents, starting materials, and intermediates used in these examples were available from commercial sources or were readily prepared by methods known to those skilled in the art.

Intermediate A. 1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. tert-Butyl-4-cyano-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate)

SCN (20.2 mL, 151 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75 mmol) and 3,4-difluoroaniline (7.5 mL, 75 mmol) in 10 mL AcOH. The reaction mixture was stirred at 100 °C for 3 h, partitioned between water and DCM and extracted three times. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was triturated with diethyl ether and the product was filtered off as a beige solid (19.25 g, 55.9 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.27 (dd, 1H), 6.84 (ddd, 1H), 6.69 (m, 1H), 6.29 (s, 1H), 3.78 (m, 2H), 3.16 (m, 2H), 2.27 (m, 2H), 1.74 (m, 2H), 1.44 (s, 9H) ppm; m/z=382.3 [M+HCO ₂ ] ^- ; t _R =1.13 minutes (LCMS method a).

Step B. tert-Butyl 4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate

Under argon, allylmagnesium bromide (1.0 M in diethyl ether, 86 mL, 86 mmol) was added dropwise to a stirred solution of tert-butyl 4-cyano-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (19.3 g, 57.1 mmol) in 300 mL THF cooled to 0 °C. The reaction mixture was brought to rt and stirred for 16 h. The mixture was acidified with 2 M aqueous HCl, diluted with DCM, washed with water and brine. The aqueous layers were extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by silica gel chromatography (0-40% MeOH in EtOAc) afforded tert-butyl 4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (7.38 g, 20.5 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.07 (dt, 1H), 6.71 (m, 1H), 6.54 (dt, 1H), 5.7 (m, 1H), 5.34 (s, 1H), 5.01 (m, 2H), 3.59 (m, 2H), 3.09 (m, 2H), 2.43 (m, 2H), 1.87 (m, 2H), 1.42 (m, 2H), 1.40 (s, 9H) ppm; mass/charge=353.2 [M+H] ⁺ ; t _R =1.32 minutes (LCMS method a).

Step C. tert-Butyl (E)-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate

Ethyl acrylate (2.5 mL, 23.0 mmol) and second-generation Hoveyda-Grubbs catalyst (656 mg, 1.05 mmol) were added under argon to a solution of tert-butyl 4-allyl-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (7.38 g, 20.9 mmol) in 200 mL of toluene. The reaction mixture was stirred for 16 h at 110 °C, cooled to rt, absorbed onto Isolute, and evaporated to dryness. Purification by silica gel chromatography (0-45% EtOAc in cyclohexane) afforded tert-butyl (E)-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate (5.00 g, 11.2 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.09 (dd, 1H), 6.76 (m, 2H), 6.56 (m, 1H), 5.86 (d, 1H), 5.50 (s, 1H), 4.07 (q, 2H), 3.59 (m, 2H), 3.08 (m, 2H), 2.64 (d, 2H), 1.88 (m, 2H), 1.48 (m, 2H), 1.40 (s, 9H), 1.20 (t, 3H) ppm; m/z=425.3 [M+H] ⁺ ; t _R =1.28 min (83%, trans), 1.30 min (14%, cis) (LCMS method a).

Step D. tert-Butyl 4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate

Under argon atmosphere, PtO ₂ (1.34 g, 0.589 mmol) was added to a solution of tert-butyl ( E )-4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobut-2-en-1-yl)piperidine-1-carboxylate (5.0 g, 11.78 mmol) in 75 mL MeOH. The reaction mixture was evacuated and flushed three times with H ₂ . The reaction mixture was then stirred for an additional 1 h at rt. Additional PtO ₂ (1.337 g, 0.589 mmol) was added and the reaction mixture was stirred for an additional 1 h at 40 °C. The reaction mixture was then flushed with argon and filtered through a pad of Hyflo® filter media. The filtrate was absorbed onto Isolute® and evaporated to dryness. Purification by silica gel chromatography (0-40% EtOAc in cyclohexane) afforded tert-butyl 4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate (4.42 g, 9.84 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.06 (dd, 1H), 6.66 (m, 1H), 6.49 (m, 1H), 5.34 (s, 1H), 4.07 and 4.00 (q, 2H), 3.57 (m, 2H), 3.06 (m, 2H), 2.21 (t, 2H), 1.89 (m, 2H), 1.64 (m, 2H), 1.4-1.5 (m, 4H), 1.40 (s, 9H), 1.20 and 1.15 (t, 3H) ppm; m/z = 427.4 [M+H] ⁺ ; t _R = 1.29 minutes (UPLC-MS method a).

Step E. 4-(1-(tert-Butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoic acid

LiOH (496 mg, 20.71 mmol) was added to a solution of tert-butyl 4-((3,4-difluorophenyl)amino)-4-(4-ethoxy-4-oxobutyl)piperidine-1-carboxylate (4.42 g, 10.35 mmol) in 40 mL of THF/water (1:1 ratio) and the reaction mixture was stirred for 16 h at 55 °C. The reaction mixture was acidified with citric acid and diluted with DCM. The aqueous layer was extracted three times with DCM. The combined organic extracts were dried with Na ₂ SO ₄ , filtered and concentrated. The resulting solid was dried under vacuum. Crude 4-(1-(tert-butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoic acid (3.81 g, 9.08 mmol) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=11.89 (br s, 1H), 7.06 (m, 1H), 6.67 (m, 1H), 6.50 (m, 1H), 5.33 (s, 1H), 3.58 (m, 2H), 3.07 (m, 2H), 2.13 (t, 2H), 1.89 (m, 2H), 1.77 (m, 2H), 1.63 (m, 2H), 1.41 (m, 2H), 1.40 (s, 9H) ppm; mass/charge=399.4 [M+H] ⁺ ; t _R =1.13 minutes (LCMS method a).

Stage F. tert-Butyl 1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate

In a solution of 4-(1-(tert-butoxycarbonyl)-4-((3,4-difluorophenyl)amino)piperidin-4-yl)butanoic acid (3.81 g, 9.56 mmol) in 100 mL of dry EtOAc was added SOCl₂(2.4 mL, 33.5 mmol) and the reaction mixture was stirred for 2 h at rt. The reaction mixture was treated with water and extracted three times with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. Purification by reversed-phase column chromatography (RP C18, 10-100% MeOH in water) gave tert-butyl 1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate (3.64 g, 9.57 mmol); m/z=381.2 [M+H]⁺;t_R=1.00 min. (LCMS method a).

Stage G. 1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

To a solution of tert-butyl 1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate (3.64 g, 9.57 mmol) in dioxane (25 mL) was added HCl (4 M in dioxane, 25 mL). The reaction mixture was stirred for 2 h at rt. The solid was collected by filtration and washed with dioxane. The HCl salt _was dissolved in water and DCM. The pH was adjusted to ~10 by adding 2 M _Na2CO3 solution. The aqueous layer was back extracted three times with DCM. The combined organic extracts were dried over _Na2CO3 , filtered and concentrated to give _1- (3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (3.00 g, 9.00 mmol). ¹ H NMR (400 MHz, DMSO- _d6 ) δ=7.46 (dd, 1H), 7.20 (m, 1H), 6.90 (m, 1H), 2.74 (m, 2H), 2.62 (m, 2H), 2.38 (t, 2H), 2.03 (m, 2H), 1.62-1.81 (m, 4H), 1.46 (m, 2H) ppm, NH not apparent; m/z=281.2 [M+H] ⁺ ; t _R = 0.49 minutes (LCMS method a).

Intermediate B. 1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. tert-Butyl 4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate)

SCN (5.97 g, 60.2 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50 mmol) and 4-chloro-3-fluoroaniline (8.77 g, 60.2 mmol) in 100 mL of acetic acid. The resulting reaction mixture was stirred for 23 h at rt. The mixture was then cooled to 0 °C and concentrated ammonium hydroxide solution was added until pH 12 was reached. The precipitate was washed with water and dried under vacuum to give tert-butyl 4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate (16.23 g, 45.0 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.35 (dd, 1H), 6.80 (d, 1H), 6.71 (d, 1H), 6.61 (s, 1H), 3.77 (m, 2H), 3.18 (m, 2H), 2.31 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H) ppm; m/z=398.3 [M+H] ⁺ ; t _R =1.22 minutes (LCMS method a).

Step B. tert-Butyl 4-allyl-4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate

tert-Butyl 4-((4-chloro-3-fluorophenyl)amino)-4-cyanopiperidine-1-carboxylate) (12 g, 33.9 mmol) was dissolved in 125 mL of dry THF and cooled to 0 °C under argon. Allylmagnesium bromide (1.0 M solution in diethyl ether, 51 mL, 51 mmol) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at 0 °C, then warmed to rt. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted three times with ethyl acetate. The organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (0-10% EtOAc in cyclohexane) afforded tert-butyl 4-allyl 4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate (7.76 g, 19.8 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.15 (dd, 1H), 6.69 (d, 1H), 6.60 (d, 1H), 5.67 (s, 1H), 5.63-5.73 (m, 1H), 4.97-5.04 (m, 2H), 4.01 (m, 1H), 3.59 (m, 2H), 3.30 (m, 1H), 2.46 (m, 2H), 1.88-1.91 (m, 2H), 1.43-1.50 (m, 2H), 1.39 (s, 9H) ppm; mass/charge=369.4 [M+H] ⁺ ; t _R =1.4 minutes (LCMS method a).

Step C. tert-Butyl 4-allyl-4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate

Tert-butyl-4-allyl-4-((4-chloro-3-fluorophenyl)amino)piperidine-1-carboxylate solution (8.54 g, 23.2 mmol) and acryloyl chloride (5.6 mL, 70 mmol) in 200 mL of toluene were heated under reflux for 1 h. Triethylamine (16.1 mL, 116 mmol) was added and the mixture was heated under reflux for 4 h. After cooling to rt, the mixture was diluted with water and extracted twice with DCM. The organic extracts were dried over Na₂SO₄, filtered and concentrated. Purification by silica gel chromatography (0-60% EtOAc in cyclohexane) afforded tert-butyl 4-allyl 4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate (5.86 g, 13.6 mmol).¹H NMR (400 MHz, DMSO-d₆) δ=7.67 (t, 1H), 7.38 (dd, 1H), 7.17-7.07 (m, 1H), 6.05 (dd, 1H), 6.02-5.84 (m, 1H), 5.67 (dd, 1H), 5.42 (dd, 1H), 5.26-5.07 (m, 2H), 3.66 (d, 2H), 3.31 (s, 3H), 3.05 (t, 1H), 2.09 (s, 2H), 1.98 (s, 1H), 1.49-1.36 (m, 1H), 1.36 (s, 9H) ppm; mass/charge=423.4 [M+H]⁺;t_R=1.36 minutes (LCMS method a).

Step D. tert-Butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate

Grubbs' II catalyst (0.859 g, 1.37 mmol) was added to a solution of tert-butyl 4-allyl 4-(N-(4-chloro-3-fluorophenyl)acrylamido)piperidine-1-carboxylate (5.8 g, 14 mmol) in 20 mL of toluene under argon. The solution was heated to 110 °C and stirred for 4 h. The reaction mixture was cooled to rt, adsorbed onto silica gel and evaporated to dryness. Purification by silica gel chromatography (0-100% EtOAc in cyclohexane) gave tert-butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (2.90 g, 6.98 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.64 (dd, 1H), 7.33 (d, 1H), 7.06 (d, 1H), 6.73 (d, 1H), 5.98 (d, 1H), 2.8-3.3 (m, 4H), 1.86 (m, 2H), 1.33 (s, 9H), 1.40-1.16 (m, 4H) ppm; m/z=395.4 [M+H] ⁺ ; t _R =1.09 minutes (LCMS method a).

Stage E. tert-Butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate

tert-Butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (2.9 g, 7.34 mmol) was dissolved in 25 mL MeOH and cooled to 0°C. NiCl was added₂⋅6 H₂O (0.476 g, 3.67 mmol) and the resulting reaction mixture was stirred for 10 min. NaBH was slowly added₄(0.556 g, 14.7 mmol) and the mixture was stirred at 0°C for 2 h. The reaction mixture was evaporated under reduced pressure. The crude product was dissolved in ethyl acetate, washed with brine and dried over Na₂SO₄Removal of the solvent under reduced pressure gave crude tert-butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate (2.54 g, 6.27 mmol), which was used in the next step without further purification.¹H NMR (400 MHz, DMSO-d₆) δ=7.62 (dd, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 3.76 (m, 2H), 2.87 (m, 2H), 2.41 (t, 2H), 2.04 (m, 2H), 1.79 (m, 4H), 1.42 (m, 2H), 1.30 (s, 9H) ppm; mass/charge=397.4 [M+H]⁺;t_R=1.08 minutes (LCMS method a).

Stage F. 1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Under argon atmosphere, trifluoroacetic acid (3.88 ml, 50.4 mmol) was added to a solution of tert-butyl 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate cooled to 0°C. (2.00 g, 5.04 mmol) in DCM (20 mL). The reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO₃and extracted three times with DCM. The combined organic extracts were dried over Na₂SO₄, filtered and concentrated. The resulting solid was triturated with diethyl ether, isolated by filtration, and dried under vacuum to give 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (1.32 g, 4.36 mmol).¹H NMR (400 MHz, DMSO-d₆) δ=8.59 (br, 1H), 7.98 (br, 1H), 7.67 (dd, 1H), 7.29 (dd, 1H), 6.99 (dd, 1H), 2.95-3.20 (m, 4H), 2.40 (t, 2H), 2.07 (m, 2H), 1.93 (m, 2H), 1.74-1.83 (m, 4H) ppm; mass/charge=297.3 [M+H]⁺;t_R=0.39 minutes (LCMS method a).

Intermediate compound C. Synthesis of 1-(4-chlorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

The title compound was synthesized analogously to intermediate B , starting from 4-chloroaniline. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.5 (br, 1H), 7.89 (br, 1H), 7.51 (d, 2H), 7.11 (d, 2H), 3.13 (m, 2H), 3.00 (m, 2H), 2.41-2.37 (m, 2H), 2.11-2.05 (m, 2H), 1.95-1.88 (m, 2H), 1.83-1.76 (m, 2H), 1.72 (m, 2H) ppm; m/z = 279.2 [M+H] ⁺ ; t _R = 0.38 minutes (LCMS method a).

Intermediate D. 1-(3,4-Difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

Step A. tert-Butyl 4-allyl-4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate

Under nitrogen atmosphere, DIEA (193 g, 1490 mmol) was added to a cooled to 0 °C solution of tert-butyl 4-allyl 4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (105 g, 298 mmol) in DCM (1.0 L). The mixture was stirred at 25 °C for 1 h. Acryloyl chloride (135 g, 1490 mmol) was added to the solution and the reaction mixture was stirred at 25 °C for 11 h. The reaction mixture was poured into water (1.0 L), then the mixture was extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (1.0 L), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Silica gel chromatography (petroleum ether:EtOAc 10:1) afforded tert-butyl 4-allyl 4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate (80.1 g, 197 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.55-7.44 (m, 1H), 7.44-7.35 (m, 1H), 7.13-7.03 (m, 1H), 6.09-5.99 (m, 1H), 5.98-5.84 (m, 1H), 5.71-5.59 (m, 1H), 5.44-5.34 (m, 1H), 5.24-5.16 (m, 1H), 5.15-5.06 (m, 1H), 3.80-3.53 (m, 2H), 3.14-2.80 (m, 4H), 2.18-1.87 (m, 2H), 1.52-1.37 (m, 2H), 1.37-1.31 (m, 9H).

Step B. tert-Butyl-1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate

To a solution of tert-butyl 4-allyl 4-(N-(3,4-difluorophenyl)acrylamido)piperidine-1-carboxylate (50 g, 123 mmol) in toluene (500 mL) was added Grubbs' catalyst II (7.70 g, 12.3 mmol) at 25 °C. The mixture was stirred at 120 °C for 12 h under N ₂ . The solution was cooled to rt, concentrated under reduced pressure and the residue was purified by silica gel chromatography (15-100% EtOAc in petroleum ether) to give tert-butyl 1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (35 g, 93 mmol) as a gray solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.52-7.41 (m, 1H), 7.39-7.29 (m, 1H), 7.07-6.96 (m, 1H), 6.76-6.64 (m, 1H), 6.02-5.90 (m, 1H), 3.90-3.65 (m, 2H), 3.01-2.79 (m, 2H), 2.78-2.73 (m, 2H), 1.90-1.79 (m, 2H), 1.39-1.25 (m, 11H); mass/charge=379.1 [M+H] ⁺

Step C. tert-Butyl-1-(3,4-difluorophenyl)-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,9-diazaspiro[5.5]undecane-9-carboxylate.

B ₂ Pin (7.4 g, 29 mmol) in THF (50 mL) was added dropwise to a stirred solution of CuCl (130 mg, 1.32 mmol), NaOt-Bu (7.60 g, 79.2 mmol), and DPEPhos (7.12 g, 13.2 mmol) in THF (50 mL) under nitrogen atmosphere. 1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undec-3-ene-9-carboxylate (10 g, 26.4 mmol) in MeOH (30 mL) was added followed by THF (20 mL). The reaction mixture was heated at 80°C for 12 h. LCMS analysis indicated complete conversion of the starting material to the pinacol boronate ester (m/z=507.2 [M+H] ⁺ ). The reaction mixture was filtered and the filtrate was used directly in the next step.

Step D. tert-Butyl 1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate

To a solution of _NaBO3⋅4H2O ( _11.7 g, 52.8 mmol) in _H2O (120 mL) was added a solution of tert-butyl 1-(3,4-difluorophenyl)-2-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,9-diazaspiro[5.5]undecane-9-carboxylate in THF from step C. The reaction mixture was then heated at 25 °C for 12 h. The mixture was poured into water (100 mL) and extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over _Na2SO4 , _filtered , and concentrated under reduced pressure. Purification by silica gel chromatography (DMC/MeOH = 1:0-10:1) gave tert-butyl 1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboxylate (6.0 g, 15 mmol) as a white solid.

Stage E. 1-(3,4-Difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

HCl in dioxane (4.0 M, 50 mL) was added to a stirred solution of tert-butyl 1-(3,4-difluorophenyl)-4-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecan-9-carboxylate (10.0 g, 25.2 mmol) in dioxane (50 mL). The reaction mixture was then heated at 25 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in MTBE (100 mL) at 25 °C for 1 h. The solids were isolated by filtration to give 1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one, hydrochloride salt (8.0 g, 24 mmol), as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.13-8.81 (m, 1H), 8.41-8.11 (m, 1H), 7.62-7.42 (m, 1H), 7.37-7.20 (m, 1H), 7.04-6.83 (m, 1H), 4.13-4.06 (m, 1H), 3.22-3.09 (m, 2H), 3.07-2.90 (m, 2H), 2.76-2.63 (m, 1H), 2.49-2.45 (m, 1H), 2.38-2.26 (m, 1H), 2.01-1.65 (m, 5H); mass/charge=297.1 [M+H] ⁺

Intermediate E. 1-(3,4-Difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

Step A. tert-Butyl 4-((3,4-difluorophenyl)amino)-4-(2,3-dihydroxypropyl)piperidine-1-carboxylate

A solution of N-methylmorpholine N-oxide (8.043 g, 68.75 mmol) in water (20 mL) was added to a stirred solution of tert-butyl 4-allyl 4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (11 g, 31 mmol) in THF (35 mL) at -7 °C under argon. A solution of OsO was added dropwise to the reaction mixture at -9 °C.₄(1.56 mmol) in t-BuOH (24 mL). The mixture was then stirred at -9°C for 12 h, after which sodium bisulfite solution was added to quench the reaction. The solution was extracted with EtOAc, the organic layer was washed with brine, dried over Na₂SO₄, filtered And concentrated to a brown sticky solid (12.2 g, 31.6 mmol). This crude material was carried to the next step without purification. m/z=387.15 [M+H]⁺

Step B. tert-Butyl 4-((3,4-difluorophenyl)amino)-4-(2-oxoethyl)piperidine-1-carboxylate

A solution of NaIO ₄ (2.64 g, 12.4 mmol) in water (20 mL) was added to a stirred solution of tert-butyl 4-((3,4-difluorophenyl)amino)-4-(2,3-dihydroxypropyl)piperidine-1-carboxylate (4.0 g, 10 mmol) in MeOH (20 mL). The reaction mixture was stirred at rt for 2 h under argon. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product as a brown sticky solid (3.17 g, 8.94 mmol). The crude product was directly carried to the next step without further purification.

Step C. tert-Butyl 4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylate

Sodium borohydride was added (0.20 g, 5.4 mmol) into a stirred solution of tert-butyl 4-((3,4-difluorophenyl)amino)-4-(2-oxoethyl)piperidine-1-carboxylate (1.6 g, 4.5 mmol) in MeOH (10 mL) at 0 °C. The reaction mixture was stirred at rt for 12 h under argon. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give crude tert-butyl 4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylate as a brown sticky mass (1.14 g, 3.20 mmol). The crude product was carried on to the next step without further purification. Mass/charge = 357.15 [M+H]⁺

Step D. tert-Butyl 4-(2-((1H-imidazole-1-carbonyl)oxy)ethyl)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate

1,1'-Carbonyldiimidazole (1.04 g, 6.40 mmol) was added to a stirred solution of tert-butyl 4-((3,4-difluorophenyl)amino)-4-(2-hydroxyethyl)piperidine-1-carboxylate (1.14 g, 3.20 mmol) in DCM (10 mL) at rt. The reaction mixture was stirred at rt for 12 h under argon. The reaction mixture was diluted with water, extracted with DCM, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude tert-butyl 4-(2-((1H-imidazole-1-carbonyl)oxy)ethyl)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate as a brown sticky solid (1.31 g, 2.91 mmol). The crude product was carried directly to the next step without purification. m/z = 451.20 [M+H] ⁺

Step E. tert-Butyl-1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate

Pyridine hydrochloride (1.00 g, 8.65 mmol) was added to a stirred solution of tert-butyl 4-(2-((1H-imidazole-1-carbonyl)oxy)-4-((3,4-difluorophenyl)amino)piperidine-1-carboxylate (1.29 g, 2.88 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 24 h under argon. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give crude tert-butyl 1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate as a sticky brown solid (1.07 g, 2.80 mmol). The crude product was carried on to the next step without further purification. W/Z = 383.1 [M+H]⁺

Step F. 1-(3,4-Difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

HCl in dioxane (4.0 M, 6.0 mL) was added to tert-butyl 1-(3,4-difluorophenyl)-2-oxo-3-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate (0.600 g, 1.57 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h under argon. The mixture was concentrated under reduced pressure. The solid was isolated by filtration, washing with diethyl ether to give the title compound (hydrochloride salt) as a pale brown solid (0.350 g, 1.24 mmol).¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.16 (s, 1H), 7.54 (dt, J=10.9, 9.0 Hz, 1H), 7.46 (ddd, J=11.6, 7.4, 2.5 Hz, 1H), 7.11 (ddt, J=8.4, 3.9, 2.0 Hz, 1H), 4.44-4.26 (m, 2H), 3.17 (d, J=13.2 Hz, 2H), 3.08-2.91 (m, 2H), 2.31 (t, J=5.5 Hz, 2H), 2.09-1.94 (m, 2H), 1.77 (td, J=13.8, 4.5 Hz, 2H); mass/charge=283.1 [M+H]⁺;t_R=1.32 minutes (LCMS mode m)

Example 1. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. (E)-Amino(2-(4-fluorophenyl)hydrazono)methanesulfonic acid

A mixture of 2-(4-fluorophenyl)1-hydrazinecarbothiamide _{(2.5 g, 14 mmol), Na2MoO4⋅2H2O (} 163 mg, _0.675 mmol), and NaCl (316 mg, 5.40 mmol) in 7 mL of water was cooled to 0 °C. 30% hydrogen peroxide solution (6.9 mL, 68 mmol) was added dropwise to the cooled suspension. The temperature was maintained below 7 °C during the first addition. The reaction then became exothermic and the temperature reached 76 °C upon cooling with an ice bath. After complete addition, the suspension was stirred with ice bath cooling for 1.5 h. The suspension was filtered and the solid was washed with 10-15 mL of chilled brine to give a beige solid (1.76 g), which was used in the next step without further purification. Mass/charge=493.3 [M+H] ⁺ ; t _R =0.38 min. (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-N'-(4-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidohydrazide

A mixture of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 1.95 g, 6.58 mmol), (E)-amino(2-(4-fluorophenyl)hydrazono)methanesulfonic acid (1.76 g, 7.56 mmol) and pyridine (1.17 mL, 14.5 mmol) in 9 mL of acetonitrile was stirred for 1 h at 120 °C under microwave irradiation. The reaction mixture was concentrated and used in the next step without further purification. m/z = 448.2 [M+H] ⁺ ; t _R = 0.67 min (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Chloro-3-fluorophenyl)-N'-(4-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidohydrazide (2.95 g, 6.58 mmol) and trimethyl orthoformate (1.5 mL, 6.58 mmol) were heated for 24 h at 90 °C under microwave irradiation. The reaction mixture was filtered through a short pad of silica gel, eluted with 20% MeOH in DCM and evaporated. Purification by silica gel chromatography (0-10% MeOH in DCM) gave the title compound (140 mg, 0.291 mmol).¹H NMR (400 MHz, DMSO-d₆) δ=8.85 (s, 1H), 7.74 (m, 2H), 7.60 (dd, 1H), 7.34 (dd, 2H), 7.24 (dd, 1H), 6.98 (d, 1H), 3.85-3.88 (m, 2H), 2.99 (t, 2H), 2.42 (m, 2H), 2.09 (m, 2H) 1.85-1.88 (m, 4H), 1.64 (td, 2H) ppm. mass/charge=458.1 [M+H]⁺;t_R=1.06 minutes (LCMS method a).

Example 2. 1-(4-Chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 80 mg, 0.27 mmol), 2-chloro-6-(trifluoromethyl)benzo[d]oxazole (60 mg, 0.27 mmol) and triethylamine (0.11 mL, 0.81 mmol) were dissolved in 1.5 mL EtOH and stirred for 30 min at 160 °C under microwave irradiation. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the title compound (49 mg, 0.097 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.73 (d, 1H), 7.59 (dd, 1H), 7.49 (dd, 1H), 7.36 (d, 1H), 7.24 (dd, 1H), 6.96 (dd, 1H), 4.04 (m, 2H), 3.36 (m, 2H) 2.45 (m, 2H), 2.15 (m, 2H), 1.95 (br d, 2H), 1.82-1.91 (m, 2H), 1.66 (m, 2H) ppm; mass/charge=482.2 [M+H] ⁺ ; t _R =1.22 minutes (LCMS method a).

Using methods similar to those described for the preparation of Example 2 using suitable commercially available chlorheterocycles and intermediate B , the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 3
1-(4-Chloro-3-fluorophenyl)-9-(4-(trifluoromethyl)pyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one 443.2; 1.19 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.59 (d, 1H), 7.56 (t, 1H), 7.20 (d, 1H), 6.93 (m, 2H), 4.50 (m, 2H), 3.07 (t, 2H), 2.45 (t, 2H), 2.16 (m, 2H), 1.86-1.93 (m, 4H), 1.49-1.56 (dt, 2H) ppm. 4
1-(4-Chloro-3-fluorophenyl)-9-(7-(trifluoromethyl)quinazolin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one 493.3; 1.31 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.22 (s, 1H), 7.97 (d, 1H), 7.65 (s, 1H), 7.53 (dd, 1H), 7.41 (dd, 1H), 7.22 (dd, 1H), 6.95 (d, 1H), 4.74 (m, 2H), 3.12 (t, 2H), 2.46 (t, 2H), 2.2 (m, 2H), 1.89-1.99 (m, 4H), 1.56 (m, 2H) ppm.

Example 5. 1-(4-Chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one

1,3-Dimethyluracil (1.855 g, 13.24 mmol) and sodium ethoxide (21% solution in EtOH, 13.6 mL, 36.4 mmol) were added to a solution of 3-(trifluoromethyl)-1H-pyrazol-5-amine (1.00 g, 6.62 mmol) in 30 mL of EtOH. The reaction mixture was stirred for 12 h at 60 °C. The mixture was concentrated, diluted with ethyl acetate, and washed with 1 M HCl (40 mL) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by silica gel chromatography (20-80% EtOAc in cyclohexane followed by 0-20% MeOH in EtOAc) gave 2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (188 mg, 0.463 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.47 (br s, 1H), 8.59 (d, J= 8Hz, 1H), 6.33-6.11 (m, 2H) ppm; m/z = 202.1 [MH] ^- , t _R = 0.65 min (LCMS method a).

Step B. 5-Chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

A mixture of POCl ₃ (5.0 mL, 54 mmol) and 2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (188 mg, 0.463 mmol) was stirred for 1 h at 80 °C. The mixture was cooled to rt and concentrated. Purification by silica gel chromatography (0-50% EtOAc in cyclohexane) gave 5-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (98 mg, 0.44 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.34 (dd, 1H), 7.43 (d, 1H), 7.31 (s, 1H) ppm; t _R = 1.03 min (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

5-Chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (95 mg, 0.43 mmol) and TEA (0.16 mL, 1.1 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 85 mg, 0.29 mmol) in 4 mL EtOH. The reaction mixture was heated for 2 h at 150 °C under microwave irradiation, evaporated, diluted with EtOAc and washed with saturated aqueous NaHCO ₃ solution and brine. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by SFC (Princeton 4-ethylpyridine, 30 x 250, 5 μm; 15-25% MeOH in CO ₂ , 10 min) gave the title compound (122 mg, 0.248 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=8.69 (dd, 1H), 7.58 (dd, 1H), 7.24 (dd, 1H), 6.96 (dd, 1H), 6.89 (d, 1H), 6.40 (s, 1H), 4.31 (m, 2H), 3.09 (t, 2H), 2.43 (t, 2H), 2.15 (m, 2H), 1.92 (m, 2H), 1.86 (m, 2H), 1.55 (m, 2H) ppm; m/z=482.3 [M+H] ⁺ ; t _R =1.14 minutes (LCMS method a).

Example 6a. 1-(4-Chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one or 1-(4-chloro-3-fluorophenyl)-9-(5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

And

Example 6b. 1-(4-Chloro-3-fluorophenyl)-9-(5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one or 1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-(4-Chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile

Cyanogen bromide (3.0 M in DCM, 1.12 mL, 3.37 mmol) was added dropwise to a solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 1.00 g, 3.37 mmol) and DIPEA (0.589 mL, 3.37 mmol) in 35 mL DCM. The reaction mixture was stirred for 1 h at rt. Brine was added to the reaction mixture. The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was used in the next step without further purification. m/z = 322.2 [M+H] ⁺ ; t _R = 0.77 min. (LCMS method a).

Stage B. 1-(4-Chloro-3-fluorophenyl)-N-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidamide

Hydroxylamine (50% in water, 0.89 mL, 15 mmol) was added to a solution of 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile (1.17 g, 3.64 mmol) in 30 mL EtOH. The reaction mixture was stirred for 1 h at 80 °C, concentrated and used in the next step without purification. m/z = 355.3 [M+H] ⁺ ; t _R = 0.47 min. (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

HOBt (926 mg, 6.05 mmol), EDC.HCl (1160 mg, 6.05 mmol) and DIPEA (1.2 mL, 7.00 mmol) were added to a solution of racemic (1R,2R)-2-(trifluoromethyl)cyclopropanecarboxylic acid (754 mg, 4.65 mmol) in DMF (30 mL). The reaction mixture was stirred for 10 min at rt. 1-(4-chloro-3-fluorophenyl)-N-hydroxy-2-oxo-1,9-diazaspiro[5.5]undecane-9-carboximidamide (1.23 g, 2.67 mmol) was added and the mixture was stirred for 72 h at rt. The mixture was concentrated, diluted with TBME and washed twice with water and brine. The organic layer _{was dried over Na2SO4 ,} filtered and concentrated. The crude product was purified by silica gel chromatography (0-6% MeOH in EtOAc) to give rac-1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one (794 mg). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.61 (dd, 1H), 7.23 (dd, 1H), 6.96 (m, 1H), 3.64 (m, 2H), 3.05 (m, 2H), 2.70 (m, 1H), 2.59 (m, 1H), 2.4 (t, 2H), 2.08 (m, 2H), 1.87-1.78 (m, 4H), 1.58-1.46 (m, 4H) ppm; m/z 473.3 [M+H] ] ⁺ ; t _R =1.14 minutes (LCMS method a). Preparative chiral HPLC (Chiralpak AD-H, 5 μm, 20 × 250 mm; mobile phase heptane:EtOH:MeOH 70:15:15; flow rate 15 mL/min; elution for 60 min) afforded Example 6a (peak 1, 304 mg, t _R = 40.6 min) and Example 6b (peak 2, 303 mg, t _R = 50.0 min).

Example 7 1-(4-Chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1,1,1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

This compound was synthesized analogously to examples 6a and 6b using 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.61 (dd, 1H), 7.23 (dd, 1H), 6.96 (dd, 1H), 3.65 (m, 2H), 3.07 (dd, 2H), 2.41 (m, 8H), 2.08 (m, 2H), 1.86-1.81 (m, 4H), 1.57-1.53 (m, 2H) ppm; m/z = 499.2 [M+H] ⁺ ; t _R = 1.24 minutes (LCMS method a).

Example 8. 1-(4-Chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(6-Chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 100 mg, 0.337 mmol) in DMF (0.5 mL) was added dropwise to a solution of trichloro-1,2,4-triazine (93 mg, 0.505 mmol) and TEA (0.094 mL, 0.674 mmol) in DMF (0.5 mL) and cooled to 0 °C. The ice bath was removed and the reaction mixture was brought to rt and stirred for 20 min. Pyrrolidine (0.28 mL, 3.4 mmol) was added and the reaction mixture was stirred for 20 min at rt. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and the remaining aqueous layer was extracted twice with EtOAc. The combined organic layers _were dried over _Na2SO4 , filtered and concentrated. Purification by silica gel chromatography (10-100% EtOAc in cyclohexane) gave 9-(6-chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (98 mg, 0.20 mmol) as a yellow powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.61 (dd, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 4.21 (m, 2H), 3.3-3.5 (m, 4H), 3.12 (t, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.8-1.95 (m, 8H), 1.7 (m, 2H) ppm; m/z=479.2 [M+H] ⁺ ; t _R =0.96 min (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

9-(6-Chloro-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (78 mg, 0.163 mmol) was dissolved in 2 mL acetic acid/0.1 mL water and heated under microwave irradiation for 11 h at 120 °C. After evaporation, the residue was dissolved in DCM and treated with triethylamine. The resulting mixture was evaporated and purified by SFC (Reprospher PEI 100Å, 5 μm, 30 × 250 mm; 14-18% MeOH in CO ₂ , 10 min). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=11.7 (s, 1H), 7.60 (t, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 5.7 (br, 1H), 4.6 (br, 1H), 3.18 (m, 4H), 3.1 (br, 2H), 2.43 (m, 2H), 2.15 (m, 2H), 1.75-1.95 (m, 8H), 1.6 (m, 2H) ppm; mass/charge=461.2 [M+H] ⁺ ; t _R =0.90 minutes (LCMS method a).

Example 9. 1-(4-Chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 3,5-dibromo-1-methylpyrazin-2(1H)-one (1 g, 3.73 mmol), 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 1.11 g, 0.373 mmol) and _K2CO3 (1.55 g, 11.2 mmol) in DMF (11 mL) was heated under microwave irradiation for 1 _h at 160°C. The reaction mixture was filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH in DCM) gave 9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (770 mg, 1.51 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.61 (dd, 1H), 7.27 (s, 1H), 7.23 (dd, 1H), 6.97 (m, 1H), 4.55 (m, 2H), 3.28 (s, 3H), 2.94 (t, 2H), 2.42 (t, 2H), 2.11 (m, 2H), 1.64-1.83 (m, 4H), 1.6-1.63 (m, 2H) ppm; m/z=483.0, 485.0 [M+H] ⁺ ; t _R =1.02 minutes (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (150 mg, 0.31 mmol), (4-fluorophenyl)boronic acid (45 mg, 0.31 mmol), K ₃ PO ₄ (132 mg, 0.62 mmol) and PdCl ₂ (dtbpf) (20 mg, 0.031 mmol) in dioxane/water 3:1 (2.7 mL) was heated at 90 °C for 20 min. The reaction mixture was then cooled, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (0-5% MeOH in DCM) gave 1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (34 mg, 0.065 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.76-7.78 (m, 2H), 7.72 (s, 1H), 7.59 (t, 1H), 7.18-7.26 (m, 3H), 6.98 (m, 1H), 4.58 (m, 2H), 3.4 (s, 3H), 2.95 (t, 2H), 2.44 (t, 2H), 2.15 (m, 2H), 1.86 (m, 4H), 1.66-1.73 (m, 2H) ppm; m/z=499.1 [M+H] ⁺ ; t _R =1.13 minutes (LCMS method a).

Example 10 9-(2-Benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(6-Chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.673 g, 2.41 mmol), 4-bromo-6-chloropyridazin-3(2 H )-one (0.500 g, 2.41 mmol) and DIPEA (1.3 mL, 7.2 mmol) in DMF (8 mL) was heated at 100 °C for 12 h. After cooling to rt, water was added and the mixture was extracted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . Filtration and concentration under reduced pressure gave crude 9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one as a pale yellow gummy solid (1.355 g), which was used without purification. Mass/charge = 272 [M+H] ⁺

Step B. 9-(2-Benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Sodium hydride (0.070 g, 2.94 mmol) and benzyl bromide (0.249 g, 1.47 mmol) were added to a stirred solution of 9-(6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.400 g, 0.980 mmol) in THF (8 mL) cooled to 0 °C. The reaction mixture was allowed to warm to rt for five hours. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (60-70% EtOAc:hexane) gave 9-(2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one as a gummy white solid (1.355 g, 2.716 mmol). m/z=499.2 [M+H] ⁺

Step C. 9-(2-Benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-(2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Solution of 9-(2-benzyl-6-chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.100 g, 0.200 mmol) and 2-Azaspiro[3.3]heptane hydrochloride (0.053 g, 0.40 mmol) in dioxane (6 ml) was stirred under argon for ten minutes. Cs₂CO₃(0.195 g, 0.600 mmol) was added to the reaction mixture under argon purge followed by addition of Pd₂(dba)₃(30 mg, 0.040 mmol) and JohnPhos (10 mg, 0.040 mmol). The mixture was heated at 100 °C for 16 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (60-70% EtOAc:hexane) afforded the title compound as a white solid (0.068 g, 0.12 mmol).¹H NMR (400 MHz, chloroform-d) δ 7.46-7.34 (m, 2H), 7.24-7.09 (m, 2H), 6.95-6.82 (m, 1H), 6.82-6.69 (m, 1H), 5.64 (s, 1H), 5.09 (s, 2H), 3.9-4.05 (m, 3H), 3.8 (s, 3H), 2.65-2.75 (m, 2H), 2.58-2.61 (m, 2H), 2.14 (t, 3H), 1.98-2.12 (m, 4H), 1.8-1.92 (m, 4H), 1.7-1.78 (m, 3H); mass/charge=560.3 [M+H]⁺;t_R=1.64 minutes (LCMS method j)

Example 11. 1-(3,4-Difluorophenyl)-9-(6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

9-(6-Chloro-3-oxo-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.200 g, 0.489 mmol) and 4-Fluorophenylboronic acid (0.342 g, 2.45 mmol) was stirred in dioxane (5 mL) and H₂O (2 ml) at rt with argon blowing for 10 min. K₃P.O.₄(0.311 g, 1.47 mmol) was added to the reaction mixture under argon purge followed by XPhosPd G2 (77 mg, 0.097 mmol). The mixture was heated under reflux at 110 °C for 48 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (LUNA Phoenomenex, 5 μm, 21.2 × 250 mm; elution with H₂O:MeCN) gave the title compound (60 mg, 0.13 mmol) as an off-white solid.¹H NMR (400 MHz, chloroform-d ) δ 11.19 (s, 1H), 7.68 (dd, 2H), 7.09-7.25 (m, 3H), 6.92 (t, 1H), 6.82 (d, 1H), 6.61 (s, 1H), 4.21 (brs, 2H), 2.91 (t, 2H), 2.62 (t, 2H), 2.10-2.19 (m, 2H), 2.03 (m, 2H), 1.93 (m2H), 1.83 (d, 2H); m/z=469.1 [M+H]⁺;t_R=1.47 minutes (LCMS method j).

Example 12. 1-(3,4-Difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 6-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-3-amine

A mixture of 6-chloropyridazin-3-amine (1.0 g, 0.77 mmol), 4-(trifluorophenyl)-1H - _pyrazole (0.210 g, 15.4 mmol) and _Cs2CO3 (0.754 g, 2.32 mmol) in dioxane (4 mL) was heated at 120 °C for 12 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over _Na2SO4 , _filtered and concentrated under reduced pressure. Purification by silica gel chromatography (35-40% EtOAC:hexane) gave 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-3-amine (0.400 g, 1.73 mmol). m/z=230.1 [M+H] ⁺

Step B. 6-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one

A mixture of 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-3-amine (0.020 g, 0.087 mmol), NaNO₂(0.012 g, 0.471 mmol) and concentrated H₂SO₄(0.5 ml) in AcOH (1 ml) was heated at 80°C for 16 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc, washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (40-50% EtOAC:hexane) gave 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one (0.010 g, 0.43 mmol). m/z=231.0 [M+H]⁺

Step C. 4-Bromo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one

A mixture of 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one (0.20 g, 0.87 mmol), KOAc (0.640 g, 6.73 mmol) and Br₂(7.0 mL, 7.4 mmol) in AcOH (2 mL) was heated at 80 °C for 24 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give crude 4-bromo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3(2H)-one (170 mg), which was used in the next step without purification.¹H NMR (400 MHz, methanol-d₄) δ 8.77 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H). mass/charge=311.0 [M+2]⁺.

Step D. 1-(3,4-Difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one.

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.090 g, 0.32 mmol), 4-bromo-6-(4-(trifluoromethyl) -1H- pyrazol-1-yl)-2-pyridazin-3( 2H )-one (0.170 g, 0.550 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (3 mL) were heated under reflux at 80 °C for 12 h. After cooling to rt, the reaction mixture was diluted with cold water, extracted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (85 mg, 0.17 mmol). ¹ H NMR (300 MHz, DMSO-d6) δ 12.8 (s, 1H), 8.88 (s, 1H), 8.22 (s, 1H), 7.46 (m, 1H), 7.29 (m, 1H), 6.9 (m, 2H), 4.16 (d, 2H), 2.96 (t, 2H), 2.41 (m, 2H), 2.04-2.18 (m, 2H), 1.83-1.91 (m, 4H), 1.61-1.76 (m, 2H); m/z=509.15 [M+H] ⁺ ; t _R =1.50 minutes (LCMS method j)

Example 13 1-(3,4-Difluorophenyl)-9-(3-oxo-6-(2,2,2-trifluoroethoxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

This compound was synthesized analogously to Example 12 using 2,2,2-trifluoroethane-1-ol. ¹ H NMR (400 MHz, DMSO-d6) δ 12.1 (s, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 6.92 (m, 1H), 6.15 (s, 1H), 4.62-4.78 (m, 2H), 4.01-4.12 (m, 2H), 2.74-2.88 (m, 2H), 2.41 (t, 2H), 2.07 (brs, 2H), 1.78-1.88 (m, 4H), 1.54-1.7 (m, 2H); m/z=473.4 [M+H] ⁺ ; t _R = 0.66 minutes (LCMS method i)

Example 14. 1-(3,4-Difluorophenyl)-9-(2-methyl-3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Iodomethane (0.018 g, 0.129 mmol) was added dropwise to a stirred solution of 1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (0.040 g, 0.078 mmol) and _Cs2CO3 (0.084 g, 0.259 mmol) _in DMF (4 mL) cooled to 0°C. _The reaction mixture was allowed to warm to rt for 4 h. Water was added to the reaction mixture and it was extracted with EtOAc, washed with brine, dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (25 mg, 0.48 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H), 8.24 (s, 1H), 7.48 (m, 1H), 7.29 (m, 1H), 6.92-7 (m, 2H), 4.12 (d, 2H), 3.6 (s, 3H), 2.98 (t, 2H), 2.42 (t, 2H), 2.08 (brs, 2H), 1.7- 1.92 (m, 4H), 1.68 (t, 2H); m/z=523.3 [M+H] ⁺ ; t _R =1.64 min (LCMS method l).

Example 15a. 1-(3,4-Difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

And

Example 15b. 9-(1-Benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-Benzyl-5-bromo-1,2-dihydropyridazine-3,6-dione and 1-benzyl-4-bromo-1,2-dihydropyridazine-3,6-dione

A mixture of 3-bromofuran-2,5-dione (5 g, 28.25 mmol) and benzylhydrazine 2HCl (8.20 g, 42.4 mmol) in water (45 mL) was heated at 100 °C for 16 h. The reaction mixture was cooled to rt and filtered. The clear filtrate was concentrated under reduced pressure to give a crude mixture of regioisomeric products (4.4 g, crude). m/z = 283 [M+2] ⁺

Step B. 2-Benzyl-4-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one and 2-benzyl-5-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one

Stirred solution of 1-benzyl-5-bromo-1,2-dihydropyridazine-3,6-dione and 1-benzyl-4-bromo-1,2-dihydropyridazine-3,6-dione (2.00 g, 7.14 mmol) in DMF (25 mL) treated with 4-bromo-tetrahydropyran (1.70 g, 10.3 mmol) and K₂CO₃(2.90 g, 20.9 mmol). The reaction mixture was heated at 85 °C for 48 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a mixture of regioisomeric products as a white sticky solid (0.576 g, 1.58 mmol). m/z=367.0 [M+H]⁺

Step-C. 9-(1-Benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and 9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of 2-benzyl-4-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one and 2-benzyl-5-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)pyridazin-3(2H)-one (100 mg, 0.273 mmol) in DMF (2 mL) was treated with 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( Intermediate A , 77 mg, 0.27 mmol) and DIPEA (72 μL, 0.41 mmol). The reaction mixture was heated at 80 °C for 48 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (YMC, 5 μm, 21.2 _x 150 mm; eluting with 0.02% aqueous _NH4OH :MeCN) to separate the two regioisomeric products.

Example 15a . 9-(2-Benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one was isolated as a pale yellow solid (115 mg, 0.203 mmol). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.3-7.47 (m, 1H), 7.22-7.30 (m, 6H), 6.94 6.96 (m, 1H), 6.08 (s, 1H), 5.03 (s, 2H), 4.72-4.81 (m, 1H), 3.9-4.05 (brs, 2H), 3.74-3.82 (m, 2H), 3.41 (t, 2H), 2.78 (t, 2H), 2.41 (t, 2H), 2.08 (m, 2H), 1.82-1.92 (m, 6H), 1.6-1.71 (m, 2H), 1.48-1.56 (m, 2H); mass/charge=565.2 [M+H]+; t _R =1.71 minutes (LCMS method l).

Example 15b . 9-(1-Benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.4-7.48 (m, 1H), 7.2-7.34 (m, 6H), 6.84-6.89 (m, 1H), 5.92 (s, 1H), 4.96 (s, 2H), 4.77-4.84 (m, 1H), 3.52-3.63 (m, 4H), 3.38-3.47 (m, 2H), 2.86 (t, 2H), 2.40 (t, 3H), 2.07 (m, 2H), 1.75-1.9 (m, 5H), 1.58-1.72 (m, 2H), 1.4-1.53 (m, 2H), m/z=565.4 [M+H]+, t _R =2.13 minutes (LCMS method l);

Example 16. 1-(3,4-Difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of 9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (100 mg, 0.177 mmol) in EtOH (15 mL) was treated with Pd(OH) ₂ (200 mg) and stirred under _H2 (1 atm) for 48 h. The reaction mixture was purged with nitrogen, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification by preparative HPLC (LUNA OMEGA C18, 5.0 μm, 21.2 × 250 mm; elution with water:MeCN) gave the title compound as an off-white solid (40 mg, 0.084 mmol). ^1H NMR (300 MHz, DMSO- _d6 ) δ 11.84 (s, 1H), 7.4-7.46 (m, 1H), 7.10-7.15 (m, 1H), 6.95-7.0 (m, 1H), 6.02 (s, 1H), 4.70-4.82 (m, 1H), 4.01 (d, 1H), 3.76-3.83 (m, 1H), 3.50-3.38 (m, 2H), 3.29-3.21 (m, 1H), 2.76 (t, 2H), 2.01-2.11 (m, 2H), 1.72-1.98 (m, 8H), 1.52-1.7 (m, 5H); mass/charge=475.4 [M+H] ⁺ ; t _R =0.45 minutes (LCMS method l).

Example 17. 1-(3,4-Difluorophenyl)-9-(2-methyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (30 mg, 0.063 mmol), _Cs2CO3 (61 mg, 0.19 mmol) and _iodomethane (6 μL, 0.096 mmol) in DMF (1 mL) was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over _Na2SO4 , _filtered and concentrated under reduced pressure. Purification by preparative HPLC (ZORBAX, 5 μm, 21.2 x 150 mm; eluting with water:ACN) gave the title compound (8 mg, 0.016 mmol) as an off-white solid. ¹ H NMR (400 MHz, chloroform-d ) δ 7.68 (dd, 1H), 7.10-7.15 (m, 1H), 6.96-7.0 (m, 1H), 6.05 (s, 1H), 4.72-4.84 (m, 1H), 3.92-4.2 (m, 2H), 3.38-3.47 (m, 4H), 2.77 (t, 2H), 2.4 (t, 2H), 2.06 (d, 2H), 1.9-2.0 (m, 2H), 1.8-1.84 (m, 4H), 1.52-1.68 (m, 4H); m/z=489.2 [M+H] ⁺ ; t _R =1.3 minutes (LCMS mode k).

Example 18. 9-(6-(4,4-Difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(6-Bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.870 g, 3.10 mmol), 5-bromo-3-chloropyrazin-2(1H)-one (0.650 g, 3.10 mmol) and DIPEA (1.6 mL, 9.3 mmol) in EtOH (10 mL) were heated at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (2-8% MeOH in DCM) gave 9-(6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one. as a white solid (0.460 g, 1.01 mmol). Mass/charge=455.05 [M+H]⁺

Step B. 9-(6-(4,4-Difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.

A mixture of 9-(6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.050 g, 0.110 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.081 g, 0.331 mmol) was stirred in DME (1 mL) and H₂O (0.5 ml) at RT with argon purge for 10 minutes. K₂CO₃(0.046 g, 0.33 mmol) was added to the reaction mixture under argon purging, followed by the addition of Pd(dppf)Cl₂·DCM (0.018 g, 0.022 mmol). The mixture was heated at 100 °C for 16 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (LUNA C18, 5 μm, 21.2 × 250 mm; elution with water:ACN) afforded the title compound (21 mg, 0.043 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 7.44 (m, 1H), 7.25 (ddd, 1H), 6.93 (m, 1H), 6.75 (s, 1H), 6.24 (s, 1H), 4.50 (d, 2H), 2.85 (m, 2H), 2.67 (m, 2H), 2.41 (m, 4H), 2.09 (m, 4H), 1.91-1.77 (m, 4H), 1.63 (m, 2H). mass/charge=491.2 [M+H]⁺;t_R=1.49 minutes (LCMS method j).

Example 19. 9-(6-(4,4-Difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.630 g, 2.24 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (0.600 g, 2.24 mmol) and DIPEA (1.2 mL, 6.7 mmol) in EtOH (8 mL) was heated at 80 °C for 12 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (2-7% MeOH in DCM) gave 9-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one as a light brown solid (0.770 g, 1.65 mmol). m/z=469.05 [M+2] ⁺

Step B. 9-(6-(4,4-Difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.

9-(6-Bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.310 g, 0.660 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.200 g, 0.820 mmol) was stirred in DME (2.5 mL) and water (1 mL) at rt under argon for 10 min. K₂CO₃(0.177 g, 1.28 mmol) was added to the reaction mixture under argon purging, followed by the addition of Pd(dppf)Cl₂·DCM (0.070 g, 0.086 mmol). The mixture was heated at 100 °C for 16 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc twice. The combined extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (Waters ATLANTIS C18, 5 μm, 21.2 x 250 mm; eluting with water/(1:1 ACN/MeOH)) gave the title compound (0.118 g, 0.233 mmol) as a brown solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.42-7.47 (m, 1H), 7.2-7.28 (m, 1H), 7.16 (s, 1H), 6.88-6.92 (m, 1H), 6.2 (m, 1H), 4.46 (d, 2H), 3.32 (s, 3H), 2.88 (t, 2H), 2.68 (t, 2H), 2.49-2.51 (m, 1H), 2.39-2.43 (m, 4H), 2.07-2.18 (m, 4H), 1.81-1.84 (m, 3H), 1.58-1.68 (m, 2H); mass/charge=505.2 [M+H]⁺;t_R=1.59 minutes (LCMS method k).

Example 20. 1-(4-Chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Stage A. 2-Cyclopentyl-2-oxoacetaldehyde

A mixture of 1-cyclopentylethanone (236 mg, 2.10 mmol) and selenium dioxide (244 mg, 2.20 mmol) in 1 mL of dioxane and 0.1 mL of water was stirred overnight at 80°C. The dark brown reaction mixture was filtered through cotton wool and washed with 4 mL of water. The filtrate was used without further purification in the next step.

Step B. 5-Cyclopentyl-3-(methylthio)-1,2,4-triazine

Sodium bicarbonate (168 mg, 2.00 mmol) was added to the reaction mixture from the previous step. The white suspension was cooled to 0-5 °C and a solution of methyl hydrazinecarbiimidothioate hydroiodide (373 mg, 1.60 mmol) in 2 mL of water was added. The reaction mixture was stirred for 2 h at 0-5 °C and then diluted with DCM and water. The organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was adsorbed onto silica gel and purified by silica gel chromatography (0-50% EtOAc in cyclohexane). m/z = 196.2 [M+H] ⁺ ; t _R = 1.02 min (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

MCPBA (134 mg, 0.584 mmol) was added to a cooled to 0 °C solution of 5-cyclopentyl-3-(methylthio)-1,2,4-triazine (100 mg, 0.486 mmol) in DMF (1 mL). The reaction mixture was warmed to rt and stirred for 1.5 h. Triethylamine (340 µL, 2.43 mmol) and 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 144 mg, 0.486 mmol) were added and the mixture was stirred at rt for two days. The solution was quenched with ice water, extracted with DCM and the extracts were concentrated. The crude product was adsorbed onto silica gel and purified by silica gel chromatography (0-50% EtOAc in cyclohexane) followed by SFC (Princeton 4-ethylpyridine 100Å, 30×250 mm, 5 μm; 9-14% MeOH in CO ₂ , 10 min) to give the title compound (28 mg, 0.060 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.54 (s, 1H), 7.58 (dd, 1H), 7.23 (d, 1H), 6.96 (d, 1H), 4.54 (m, 1H), 4.08 (m, 2H), 3.18 (m, 4H), 3.05 (m, 3H), 2.45 (t, 2H), 2.18 (m, 2H), 1.9 (m, 4H), 1.5-1.7 (m, 5H) ppm; m/z=444.2 [M+H] ⁺ ; t _R =1.16 minutes (LCMS method a).

Example 21. 1-(4-Chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 5-(4-Fluorophenyl)oxazole

Tosyl methyl isocyanate (787 mg, 3.95 mmol) and K ₂ CO ₃ (655 mg, 4.74 mmol) were added to a solution of 4-fluorobenzaldehyde (0.425 mL, 3.95 mmol) in 20 mL MeOH. The reaction mixture was stirred for 3 h at 80 °C, then 16 h at rt. The reaction mixture was concentrated, diluted with water and extracted three times with ethyl acetate. The organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (10-60% EtOAc in cyclohexane) gave 5-(4-fluorophenyl)oxazole (539 mg, 3.14 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=8.45 (s, 1H), 7.78 (m, 2H), 7.68 (s, 1H), 7.34 (m, 2H) ppm; m/z=164.1 [M+H] ⁺ ; t _R =0.88 minutes (LCMS method d).

Step B. 2-Chloro-5-(4-fluorophenyl)oxazole

LiHMDS (1.0 M in THF, 1.53 mL, 1.53 mmol) was added dropwise to a -78 °C cooled solution of 5-(4-fluorophenyl)oxazole (200 mg, 1.23 mmol) in 10 mL THF. The reaction mixture was stirred for 30 min at -78 °C. This solution was then added dropwise to a suspension of hexachloroethane (580 mg, 2.45 mmol) in 5 mL THF at -78 °C. The reaction mixture was allowed to warm to rt and stirred at this temperature for an additional 12 h. The mixture was quenched with saturated aqueous NH ₄ Cl and extracted twice with EtOAc. The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel chromatography (50-100% DCM in cyclohexane) to afford 2-chloro-5-(4-fluorophenyl)oxazole (61 mg, 0.31 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.78 (s, 1H), 7.75 (m, 2H), 7.36 (m, 2H) ppm; m/z = no molecular ion detected; t _R = 1.09 minutes (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-chloro-5-(4-fluorophenyl)oxazole (57 mg, 0.288 mmol), triethylamine (0.11 mL, 0.81 mmol), and 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 80 mg, 0.27 mmol) in 4 mL EtOH was stirred for 3 h at 160 °C. After cooling to rt, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by SFC (Princeton 2-ethylpyridine 100Å, 5 μm, 30×250 mm; 13-18% MeOH in CO ₂ , 13 min) gave the title compound (76 mg, 0.17 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.61 (dd, 1H), 7.54 (dd, 2H), 7.27 (dd, 1H), 7.24 (s, 1H), 7.22 (dd, 2H), 6.98 (dd, 1H), 4.89 (m, 2H), 3.17 (m, 2H), 2.43 (t, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.84 (m, 2H), 1.61 (m, 2H) ppm; m/z=458.3 [M+H] ⁺ ; t _R =1.12 minutes (LCMS method a).

Example 22. 1-(4-Chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-(4-Chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of sodium azide (515 mg, 7.92 mmol), triethylamine hydrochloride (1.09 g, 7.92 mmol), and 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile (850 mg, 2.64 mmol) in 10 mL of DMF was heated under microwave irradiation for 2 h at 130 °C. The reaction mixture was filtered, diluted with EtOAc, and the pH was adjusted to 5 with 4 N HCl. The aqueous layer was extracted twice with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated. Purification by silica gel chromatography (0-30% MeOH in DCM) gave 1-(4-chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=14.95 (br s, 1H), 7.60 (dd, 1H), 7.26 (d, 1H), 6.98 (dd, 1H), 3.67 (m, 2H), 3.17 (t, 2H), 2.43 (t, 2H), 2.09 (m, 2H), 1.8-1.88 (m, 4H), 1.62 (m, 2H) ppm; mass/charge=365.2 [M+H] ⁺ ; t _R = 0.65 minutes (LCMS method a).

Step C. 1-(4-Chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Under argon atmosphere _{, K2CO3} (62.5 mg, 0.452 mmol), [Cu(OH)( ™ EDA)] _2Cl2 ( ₂₃ mg, 0.049 mmol) and phenylboronic acid (158 mg, 1.23 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-9-(1H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 150 mg, 0.411 mmol) in 3 mL DCM. The resulting mixture was momentarily placed under vacuum before adding a balloon of _O2 and stirring at rt for 48 h. The reaction mixture was filtered through celite and concentrated. Purification by silica gel chromatography (0-5% MeOH in DCM) gave the title compound (32 mg, 0.070 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.93 (d, 2H), 7.58-7.62 (m, 3H), 7.51 (t, 1H), 7.26 (dd, 1H), 6.98 (d, 1H), 3.90 (m, 2H), 3.17-3.19 (m, 2H), 2.45 (t, 2H), 2.13 (m, 2H), 1.86-1.95 (m, 4H), 1.6-1.75 (m, 2H) ppm; mass/charge=441.2 [M+H] ⁺ ; t _R = 1.19 minutes (LCMS method a).

Example 23. 1-(4-Chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 3-Chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole

A mixture of 3,5-dichloro-1,2,4-thiadiazole (150 mg, 0.968 mmol), 3,3-difluoropyrrolidine hydrochloride (167 mg, 1.16 mmol) and triethylamine (0.67 mL, 4.8 mmol) in EtOH (1.5 mL) was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na₂SO₄, filtered and evaporated. Purification by silica gel chromatography (0-15% EtOAc in cyclohexane) gave 3-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole (165 mg, 0.731 mmol) as a white crystalline solid.¹H NMR (400 MHz, DMSO-d₆) δ=3.95 (t, 2H), 3.70 (m, 2H), 2.6-2.7 (m, 2H) ppm; mass/charge=226.0 [M+H]⁺;t_R=0.84 minutes (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 100 mg, 0.337 mmol), 3-chloro-5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazole (114 mg, 0.505 mmol) and triethylamine (0.14 mL, 1.0 mmol) in DMF (1.5 mL) was heated under microwave irradiation for 3 h at 160 °C. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. SFC purification (Waters Atlantis HILIC silica, 30 x 250 mm, 5 μm, 11-16% MeOH in CO ₂ , 10 min) gave the title compound (29 mg, 0.059 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.60 (t, 1H), 7.23 (dd, 1H), 6.95 (dd, 1H), 4.05 (m, 2H), 3.8 (m, 2H), 3.55 (t, 2H), 3.0 (m, 2H), 2.55 (m, 2H), 2.45 (t, 2H), 2.1 (m, 2H), 1.8-1.9 (m, 4H), 1.45-1.6 (m, 2H) ppm; m/z=486.2 [M+H] ⁺ ; t _R =1.10 minutes (LCMS method a).

Using methods similar to those described for the preparation of Example 23 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 24
1-(4-Chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)azetidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one 504.1; 1.14 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.62 (t, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 4.25 (t, 2H), 4.0-4.1 (m, 4H), 3.8 (m, 1H), 3.01 (m, 2H), 2.43 (t, 2H), 2.10 (m, 2H), 1.80-1.85 (m, 4H), 1.56 (m, 2H) ppm 25
1-(4-Chloro-3-fluorophenyl)-9-(5-(pyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one 450.5; 1.09 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.62 (t, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 4.09 (m, 2H), 3.25 (m, 4H), 3.00 (m, 2H), 2.45 (t, 2H), 2.10 (m, 2H), 1.93 (m, 4H), 1.8 (m, 4H), 1.51 (m, 2H) ppm

Example 26. 1-(4-Chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. Bis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine

Benzotriazole (5.96 g, 50 mmol) was dissolved in EtOH (100 mL) and stirred at 0 °C. A solution of BrCN (2.656 g, 25 mmol) in 10 mL of acetone was added followed by aqueous NaOH (8.0 M, 3.1 mL, 25 mmol). The resulting suspension was stirred for 20 min at 0 °C. The white precipitate was filtered, washed with ice-cold EtOH and dried under reduced pressure to give crude bis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine. m/z = 264.2 [M+H] ⁺ ; t _R = 0.92 min (LCMS method a).

Step B. 9-((1H-Benzo[d][1,2,3]triazol-1-yl)(imino)methyl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A suspension of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 100 mg, 0.337 mmol) in THF (1 mL) was added dropwise to a suspension of bis(1H-benzo[d][1,2,3]triazol-1-yl)methanimine in dry THF (2.5 mL). The reaction mixture was stirred overnight at rt, diluted with DCM, washed with Na ₂ CO ₃ solution, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was used in the next step without further purification. m/z = 441.2 [M+H] ⁺ ; t _R = 0.65 min (LCMS method a).

Step C. (E)-N-((1H-Benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide

4-Fluorobenzoyl chloride (37 mg, 0.23 mmol) and TEA (32 µL, 0.23 mmol) were added to a solution of 9-((1H-benzo[d][1,2,3]triazol-1-yl)(imino)methyl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (170 mg, 0.231 mmol) in DCM (2.5 mL). The resulting mixture was stirred overnight at rt, diluted with DCM and washed with water. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (0-100% EtOAc in cyclohexane followed by 0-10% MeOH in DCM) gave (E)-N-((1H-benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide (31 mg, 0.05 mmol). m/z = 563.3 [M+H] ⁺ ; t _R = 1.10 min (LCMS method a).

Step D. 1-(4-Chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one

Hydrazine (1.0 M in THF, 0.06 mL, 0.06 mmol) was added to a solution of (E)-N-((1H-benzo[d][1,2,3]triazol-1-yl)(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)methylene)-4-fluorobenzamide (34 mg, 0.06 mmol) in DCM (0.5 mL). After stirring overnight at rt, additional hydrazine (1.0 M in THF, 0.06 mL, 0.06 mmol) was added and stirring was continued for an additional hour. _The reaction mixture was diluted with DCM, washed with aqueous _Na2CO3 , dried over _Na2SO4 , _filtered and concentrated. Purification by silica gel chromatography (0-20% MeOH in DCM) gave the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.55 (s, 1H), 7.90 (dd, 2H), 7.60 (t, 1H), 7.24 (m, 3H), 6.98 (d, 1H), 3.75 (m, 2H), 3.0 (m, 2H), 2.43 (t, 2H), 2.10 (m, 2H), 1.85 (m, 4H), 1.63 (m, 2H) ppm; m/z = 458.2 [M+H] ⁺ ; t _R = 0.96 minutes (LCMS method a).

Example 27. 1-(4-Chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Methanesulfonic acid (0.017 mL, 0.26 mmol) was added to a mixture of 1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecane-9-carbonitrile (140 mg, 0.435 mmol), 2-picoline N-oxide (47 mg, 0.44 mmol), Ph ₃ PAuNTf ₂ (2:1 toluene adduct, 17 mg, 0.019 mmol) and ethynylcyclohexane (0.028 mL, 0.218 mmol) in 2 mL of chlorobenzene. The reaction mixture was stirred for 16 h at 60 °C. After cooling to rt, the mixture was diluted with DCM and washed with 5% K ₂ CO ₃ solution and brine. The organic layer was dried over _Na2SO4 , _filtered and concentrated. Purification by silica gel chromatography (0-10% MeOH in DCM) followed by SFC (Reprospher PEI 100Å, 5 μm, 30×250 mm; 7-17% MeOH in _CO2 , 10 min) gave the title compound (7 mg, 0.012 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=7.60 (dd, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 6.33 (d, 1H), 3.68 (m, 2H), 3.03 (t, 2H), 2.41 (t, 2H), 2.07 (m, 2H), 1.80-1.84 (m, 5H), 1.56-1.67 (m, 6H), 1.15-1.29 (m, 6H) ppm; m/z=446.4 [M+H] ⁺ ; t _R =1.23 minutes (LCMS method a).

Example 28. 1-(4-Chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 5-phenyl-1,3,4-oxadiazole-2-thiol (54 mg, 0.303 mmol) and 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 90 mg, 0.30 mmol) in EtOH (0.8 mL) was heated under microwave irradiation for 8 h at 160 °C. After cooling to rt, the reaction mixture was concentrated. SFC purification (Reprosphere PEI 100 Å, 30 x 250, 5 μm, 11-16% MeOH in CO ₂ , 10 min) gave the title compound (33 mg, 0.071 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.82-7.86 (m, 2H), 7.61 (t, 1H), 7.51 (m, 3H), 7.26 (dd, 1H), 6.99 (d, 1H), 3.83 (m, 2H), 3.29 (m, 2H), 2.45 (t, 2H), 2.13 (m, 2H), 1.95 (m, 2H), 1.86 (m, 2H), 1.68 (m, 2H) ppm; m/z=441.2 [M+H] ⁺ ; t _R =0.99 minutes (LCMS method a).

Example 29. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-(4-Fluorophenyl)-1H-1,2,3-triazole

Propiolic acid (0.20 mL, 3.3 mmol), sodium ascorbate (174 mg, 0.875 mmol), DBU (0.17 mL, 1.1 mmol) and copper(I) iodide (83 mg, 0.44 mmol) were added to a solution of 1-azido-4-fluorobenzene (4.38 mL, 2.19 mmol) in DMF (10 mL). The reaction mixture was stirred for 3 h at 60 °C, cooled to rt, diluted with EtOAc and washed with water. The organic layer was dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (20-70% EtOAc in cyclohexane) gave 1-(4-fluorophenyl)-1H-1,2,3-triazole (295 mg, 1.77 mmol) as a yellow solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.82 (d, 1H), 7.98 (d, 1H), 7.97-7.91 (m, 2H), 7.48-7.45 (m, 2H) ppm; m/z = 164.1 [M+H] ⁺ ; t _R = 0.70 minutes (LCMS method a).

Step B. 1-(4-Fluorophenyl)-1H-1,2,3-triazole-3-oxide

MCPBA (402 mg, 2.33 mmol) was added to a solution of 1-(4-fluorophenyl)-1H-1,2,3-triazole (292 mg, 1.79 mmol) in EtOAc (2 mL). The reaction mixture was stirred for 72 h at rt. The mixture was diluted with DCM and washed with 1 M NaOH. The organic layer was dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (80-100% EtOAc in cyclohexane followed by 0-20% MeOH in DCM) gave 1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (177 mg, 0.988 mmol) as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=8.92 (d, 1H), 7.94 (d, 1H), 7.87-7.80 (m, 2H), 7.50-7.42 (m, 2H) ppm; m/z=180.1 [M+H] ⁺ ; t _R =0.46 minutes (LCMS method a).

Step C. 4-Bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide

Bromine (0.204 mL, 3.95 mmol) was added dropwise to a solution of 1-(4-fluorophenyl)-1H-1,2,3- _triazole 3-oxide (177 mg, 0.988 mmol) and _Na2CO3 (209 mg, 1.98 mmol) in a mixture of _CHCl3 (0.6 mL) and water (0.8 mL) cooled to 0 °C. The reaction mixture was stirred for 12 h at rt. 10% aqueous sodium thiosulfate solution was added and stirring was continued for 30 min at rt. The mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried _{over Na2SO4} and concentrated. Purification by silica gel chromatography (0-6% MeOH in DCM) gave 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (204 mg, 0.791 mmol) as a white crystalline solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 9.24 (s, 1H), 7.85-7.78 (m, 2H), 7.52-7.43 (m, 2H) ppm. m/z = 258.1, 260.1 [M+H] ⁺ ; t _R = 0.59 min (LCMS method a).

Step D. 4-Bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole

PCl ₃ (2.00 mL, 22.9 mmol) was added to 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole 3-oxide (200 mg, 0.775 mmol) and the reaction mixture was stirred for 1 h at 80 °C. The mixture was quenched with water and extracted twice with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The resulting crude 4-bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole (177 mg) was used in the next step without further purification. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=9.12 (s, 1H), 7.98-7.92 (m, 2H), 7.54-7.45 (m, 2H) ppm; m/z=242.1, 244.1 [M+H] ⁺ ; t _R =0.94 minutes (LCMS method a).

Step E. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

4-Bromo-1-(4-fluorophenyl)-1H-1,2,3-triazole (80 mg, 0.329 mmol), BrettPhos Precat G1 (22.42 mg, 0.025 mmol) and sodium tert-butoxide (60.7 mg, 0.632 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 75 mg, 0.253 mmol) in dioxane (3 mL). The reaction mixture was heated under microwave irradiation for 2 h at 120 °C, cooled to rt, evaporated, diluted with EtOAc and washed with saturated aqueous NaHCO ₃ . The organic layer was dried over _Na2SO4 and concentrated. SFC purification (Princeton 4-ethylpyridine 60Å, 30×250 mm, 5 μm, 5-25% MeOH in _CO2 , 17 min) gave the title compound (8 mg, 0.02 mmol) as a _white solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=8.11 (s, 1H), 7.87-7.81 (m, 2H), 7.62 (dd, 1H), 7.42 (dd, 2H), 7.27 (dd, 1H), 7.00 (m, 1H), 3.55 (m, 2H), 2.87 (m, 2H), 2.43 (t, 2H), 2.08 (m, 2H), 1.90-1.82 (m, 4H), 1.72 (m, 2H) ppm; m/z=458.1 [M+H] ⁺ ; t _R =1.05 minutes (LCMS method a).

Example 30. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-(4-Fluorophenyl)-3-iodo-1H-pyrazole

1-Fluoro-4-iodobenzene (0.476 mL, 4.08 mmol), CuI (13 mg, 0.068 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0.043 mL, 0.27 mmol) and _K2CO3 (564 _mg , 4.08 mmol) were added to a solution of 3-bromo-1H-pyrazole (200 mg, 1.36 mmol) in toluene (12 mL). The reaction mixture was stirred for 72 h at 100 °C, cooled to rt, concentrated, _{diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and} concentrated. Purification by silica gel chromatography (0-20% EtOAc in cyclohexane) gave 1-(4-fluorophenyl)-3-iodo-1H-pyrazole (204 mg, 0.673 mmol) as a pale yellow solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 8.40 (d, 1H), 7.83 (m, 2H), 7.35 (m, 2H), 6.78 (d, 1H) ppm; m/z = 289.1 [M+H] ⁺ ; t _R = 1.13 minutes (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Fluorophenyl)-3-iodo-1H-pyrazole (93 mg, 0.323 mmol), BrettPhos Precat G1 (24 mg, 0.027 mmol) and sodium tert-butoxide (78 mg, 0.81 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 80 mg, 0.27 mmol) in dioxane (4 mL). The reaction mixture was heated under microwave irradiation for 12 h at 100 °C, cooled to rt, concentrated, diluted with EtOAc and washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. SFC purification (Reprospher PEI, 30 x 205 mm, 5 μm, 10-15% MeOH in CO ₂ , 10 min) gave the title compound (39 mg, 0.083 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.21 (s, 1H), 7.67 (m, 2H), 7.61 (m, 1H), 7.24 (m, 3H), 6.98 (m, 1H), 6.01 (s, 1H), 3.60 (m, 2H), 2.85 (t, 2H), 2.42 (m, 2H), 2.07 (m, 2H), 1.85 (m, 4H), 1.67 (m, 2H) ppm; m/z=457.4 [M+H] ⁺ ; t _R =1.21 minutes (LCMS method a).

Example 31. 1-(4-Chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-(4-Fluorophenyl)-4-nitro-2H-1,2,3-triazole

(4-Fluorophenyl)boronic acid (6.13 g, 43.8 mmol), copper(II)-acetate (5.97 g, 32.9 mmol) and pyridine (3.6 mL, 44 mmol) were added to a solution of 4-nitro-2H-1,2,3-triazole (2.50 g, 21.9 mmol) in DCE (70 mL). The reaction mixture was stirred for 12 h at _{rt, filtered through a pad of celite, diluted with DCM and washed with water, NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and concentrated} . Purification by silica gel chromatography (0-30% EtOAc in cyclohexane) gave 2-(4-fluorophenyl)-4-nitro-2H-1,2,3-triazole (930 mg, 4.47 mmol) as a white solid. m/z=no molecular ion detected; t _R = 1.05 min (LCMS method a).

Stage B. 2-(4-Fluorophenyl)-2H-1,2,3-triazol-4-amine

Acetic acid (2.6 mL, 45 mmol) and iron (1.25 g, 22.3 mmol) were added to a solution of 2-(4-fluorophenyl)-4-nitro-2H-1,2,3-triazole (930 mg, 4.47 mmol) in THF (30 mL). The reaction mixture was stirred for 12 h at 80 °C. Additional AcOH (2.56 mL, 44.7 mmol) and iron (500 mg, 8.95 mmol) were added and the mixture was stirred for 3 h at 80 °C. The mixture was filtered through a pad of celite, diluted with EtOAc and washed with saturated NaHCO ₃ solution and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (0-56% EtOAc in cyclohexane) gave 2-(4-fluorophenyl)-2H-1,2,3-triazol-4-amine (690 mg, 3.37 mmol) as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ = 7.80 (m, 2H), 7.32 (m, 2H), 7.25 (s, 1H), 5.52 (br s, 2H) ppm; m/z = 179.1 [M+H] ⁺ ; t _R = 0.80 minutes (LCMS method a).

Step C. 4-Bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole

A solution of 2-(4-fluorophenyl)-2H-1,2,3-triazol-4-amine (300 mg, 1.68 mmol) in 7 mL of acetonitrile was added dropwise to a solution of copper(II) bromide (451 mg, 2.02 mmol) and tert-butyl nitrite (0.36 mL, 2.7 mmol) in acetonitrile (7 mL). The reaction mixture was stirred for 2 h at rt, diluted with EtOAc and washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. Purification by silica gel chromatography (0-24% EtOAc in cyclohexane) gave 4-bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole (330 mg, 1.27 mmol). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=8.35 (s, 1H), 8.01 (m, 2H), 7.43 (m, 2H) ppm; t _R =0.80 minutes (LCMS method a)

Step D. 1-(4-Chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

4-Bromo-2-(4-fluorophenyl)-2H-1,2,3-triazole (73.4 mg, 0.303 mmol), BrettPhos Precat G1 (29.9 mg, 0.034 mmol) and sodium tert-butoxide (81 mg, 0.842 mmol) were added to a solution of 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B , 100 mg, 0.337 mmol) in dioxane (3 mL). The reaction mixture was heated under microwave irradiation for 3 h at 120 °C, cooled to rt, concentrated, diluted with EtOAc and washed with saturated NaHCO ₃ solution and brine. The organic layer _{was dried over Na2SO4 and} concentrated. Purification by silica gel chromatography (50-100% EtOAc in cyclohexane followed by 0-5% MeOH in EtOAc) followed by SFC (Reprosil NH2, 5 μm, 30 x 250 mm; 18-23% MeOH in _CO2 , 10 min) gave the title compound (8 mg, 0.02 mmol) as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ=7.83 (dd, 2H), 7.61 (m, 2H), 7.32 (dd, 2H), 7.27 (dd, 1H), 6.99 (d, 1H), 3.62 (m, 2H), 2.98 (m, 2H), 2.43 (t, 2H), 2.09 (m, 2H), 1.82-1.88 (m, 4H), 1.66-1.72 (m, 2H) ppm; m/z=458.3 [M+H] ⁺ ; t _R =1.27 minutes (LCMS method a).

Example 32. 1-(4-Chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-Chloro-6-(4-fluorophenyl)pyridine

2-Bromo-6-chloropyridine (1.00 g, 5.19 mmol), (4-fluorophenyl)boronic acid (1.09 g, 7.79 mmol) and 2 M _Na2CO3 (2 mL, 4 mmol) were dissolved in 10 mL of toluene/ _EtOH and purged with argon for 30 min. Then Pd( _PPh3 ) ₄ (300 mg, 0.25 mmol) was added and the reaction mixture was stirred for 12 h at 100°C. After cooling to rt, the reaction mixture was concentrated. Purification by silica gel chromatography (1-2% EtOAc in petroleum ether) gave 2-chloro-6-(4-fluorophenyl)pyridine. m/z = 184.1 [M+H] ⁺ , t _R = 2.23 min. (LCMS method a)

Step B. 1-(4-Chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

2-Chloro-6-(4-fluorophenyl)pyridine (50 mg, 0.241 mmol), 1-(4-chlorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate C , 99 mg, 0.27 mmol) and NaOtBu (35 mg, 0.36 mmol) were dissolved in 10 mL of toluene/EtOH and purged with argon for 30 min. Then Pd ₂ (dba) ₃ (12 mg, 0.012 mmol) and Dave-phos (10 mg, 0.024 mmol) were added and the reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was cooled to rt and concentrated. Preparative HPLC purification gave the title compound (14 mg, 0.030 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.03 (dd, 2H), 7.55 (dd, 1H), 7.42 (d, 2H), 7.25 (dd, 2H), 7.14 (d, 1H), 7.09 (d, 2H), 6.70 (d, 1H), 4.25 (m, 2H), 2.95 (br t, 2H), 2.44 (t, 2H), 2.13 (m, 2H), 1.85-1.90 (m, 4H), 1.57-1.64 (dt, 2H) ppm; mass/charge=450.2 [M+H] ⁺ ; t _R =2.38 minutes (LCMS method d)

Example 33. 2-(1-(4-Chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide

Step A. 4-Bromo-2-chloropyridine-1-oxide

MCPBA (1.569 g, 9.09 mmol) was added portionwise to a solution of 4-bromo-2-chloropyridine (0.50 g, 2.6 mmol) in DCM (24 mL). The reaction mixture was stirred overnight at 50 °C, cooled to rt, diluted with EtOAc and washed with water, saturated aqueous sodium bisulfite solution and NaHCO ₃ solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (50-75% EtOAc in cyclohexane) followed by SFC (Reprosphere PEI 100Å, 5 μm, 30 × 250 mm; 2-7% MeOH in CO ₂ , 10 min) gave 4-bromo-2-chloropyridine-1-oxide (78 mg, 0.37 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.36 (d, 1H), 8.19 (d, 1H), 7.66 (dd, 1H) ppm; m/z = 208.0, 210.0, 212.0 [M+H] ⁺ ; t _R = 0.45 minutes (LCMS method a)

Step B. 4-Bromo-2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridin-1-oxide

1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate B, 111 mg, 0.374 mmol) and NaHCO ₃ (29 mg, 0.34 mmol) were added to a solution of 4-bromo-2-chloropyridine 1-oxide (65 mg, 0.31 mmol) in 1 mL tert-amyl alcohol. The reaction mixture was heated under reflux overnight at 110 °C. After cooling to rt, the mixture was diluted with EtOAc and washed with water. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% EtOAc in cyclohexane). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.99 (d, 1H), 7.65 (dd, 1H), 7.29 (d, 1H), 7.14-7.16 (m, 2H), 7.01 (d, 1H), 3.76 (m, 2H), 2.84 (br t, 2H), 2.43 (t, 2H), 2.10-2.18 (m, 2H), 1.8-1.9 (m, 4H), 1.7 (m, 2H) ppm; m/z=468.2, 470.2 [M+H] ⁺ ; t _R =0.80 min (LCMS method a).

Step C. 2-(1-(4-Chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide

K ₃ PO ₄ (160 mg, 0.755 mmol) and PdCl ₂ (dtbpf) (16 mg, 0.025 mmol) were added to a solution of 4-bromo-2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine 1-oxide (118 mg, 0.250 mmol) and 4-fluorophenylboronic acid pinacol ester (56 mg, 0.25 mmol) in 1.3 mL of dioxane and 0.43 mL of water. The reaction mixture was heated under microwave irradiation for 45 min at 110 °C. After cooling to rt, the mixture was concentrated. Purification by silica gel chromatography (0-7% MeOH in DCM) gave the title compound (52 mg, 0.11 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.12 (d, 1H), 7.83 (d, 1H), 7.82 (d, 1H), 7.66 (t, 1H), 7.2-7.35 (m, 5H), 7.03 (d, 1H), 3.84 (m, 2H), 2.87 (br t, 2H), 2.43 (t, 2H), 2.15 (m, 2H), 1.8-1.9 (m, 4H), 1.7-1.8 (m, 2H) ppm; m/z=484.3 [M+H] ⁺ ; t _R = 0.92 minutes (LCMS method a).

Example 34. 4-(3-Chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridine-1-oxide

The title compound was synthesized analogously to Example 33 , starting from 2-chloro-4-(3-chlorophenoxy)pyridine. ¹ H NMR (300 MHz, DMSO-d6) δ 8.02 (d, 1H), 7.56-7.41 (m, 2H), 7.35-7.21 (m, 3H), 7.07-7.10 (m, 1H), 6.95-6.98 (m, 1H), 6.66 (d, 1H), 6.57 (dd, 1H), 3.83 (d, 2H), 2.77 (t, 2H), 2.41 (t, 2H), 2.02-2.12 (m, 2H), 1.62-1.86 (m, 6H); mass/charge=500.2 [M+H] ⁺ ; t _R =1.34 minutes (LCMS method l)

Example 35a. 9-(2-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

And

Example 35b. 9-(4-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-Chloro-4-(5-azaspiro[2.3]hexan-5-yl)pyrimidine and 5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane

A mixture of 2,4-dichloropyrimidine (96 mg, 0.52 mmol), 5-azaspiro[2.3]hexane (60 mg, 0.47 mmol), and triethylamine (65 µL, 0.47 mmol) in DMF (1.5 mL) was stirred for 18 h at rt. Silica gel chromatography (ethyl acetate) afforded a mixture of 5-(2-chloropyrimidin-4-yl)-5-azaspiro[2.3]hexane and 5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane, which was used directly in the next step. W/Z=195.9.

Step B. 9-(2-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and 9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 5-(2-chloropyrimidin-4-yl)-5-azaspiro[2.3]hexane and 5-(4-chloropyrimidin-2-yl)-5-azaspiro[2.3]hexane from step A, 1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate B, 111 mg, 0.375 mmol) and triethylamine (0.16 mL, 1.1 mmol) in 1 mL of EtOH was stirred in the microwave for 1 h at 160°C. The reaction mixture was concentrated and the crude products were purified by silica gel chromatography (0-15% MeOH in DCM) followed by preparative HPLC (XBridge Phenyl OBD, 5 μm, 30 × 100 mm; mobile phase A: 0.1% NH4OH, mobile phase B: ACN; 30 mL/min; 28-58% ACN for 15 min) to afford the regioisomeric products:

Example 35a . 9-(2-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.73 (d, J=6.36 Hz, 1 H) 7.51 (t, J=8.38 Hz, 1 H) 7.07 (dd, J=9.90, 2.20 Hz, 1 H) 6.93 (dt, J=8.44, 1.04 Hz, 1 H) 6.01 (d, J=6.36 Hz, 1 H) 4.30 (br d, J=12.35 Hz, 2 H) 4.04 (s, 4 H) 3.01 (br t, J=12.41 Hz, 2 H) 2.57 (t, J=6.79 Hz, 2 H) 2.24 (br s, 2 H) 1.86-2.02 (m, 4 H) 1.62-1.75 (m, 2 H) 0.66 (s, 4 H); mass/charge = 456.2 [M+H] ⁺ ; t _R = 0.77 minutes (LCMS method a).

Example 35b . 9-(4-(5-Azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.73 (d, J=5.87 Hz, 1 H) 7.49 (t, J=8.15 Hz, 1 H) 7.06 (dd, J=9.90, 2.20 Hz, 1 H) 6.91 (d, J=8.68 Hz, 1 H) 5.63 (d, J=5.99 Hz, 1 H) 4.41-4.55 (m, 2 H) 3.96-4.09 (m, 4 H) 2.90-3.00 (m, 2 H) 2.57 (t, J=6.79 Hz, 2 H) 2.16-2.28 (m, 2 H) 1.81-2.04 (m, 4 H) 1.67 (td, J=12.65, 4.40 Hz, 2 H) 0.63-0.71 (m, 4 H); mass/charge=456.3 [M+H] ⁺ ; t _R =0.81 minutes (LCMS method a).

Using methods similar to those described for the preparation of Examples 35a and 35b using the appropriate spirocyclic piperidine intermediates and commercially available amines for Step A, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 36
1-(4-Chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 462.1; 1.12 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.78 (d, 1H), 7.6 (t, 1H), 7.23 (dd, 1H), 6.96 (dd, 1H), 3.95 (m, 2H), 3.5 (m, 4H), 3.05 (m, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.82 (m, 8H) 1.6 (m, 2H).ppm 37
1-(4-Chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 516.2; 1.12 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.82 (d, 1H), 7.6 (t, 1H), 7.22 (dd, 1H), 6.96 (dd, 1H), 4.31 (m, 2H), 4.0-4.1 (m, 4H), 3.7 (m, 1H), 3.08 (m, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.82 (m, 4H), 1.5-1.6 (m, 2H).ppm 38
1-(4-Chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one 445.2 ^; ; 0.97 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.01 (s, 1H), 7.58 (t, 1H), 7.22 (d, 1H), 6.95 (d, 1H), 4.56 (m, 2H), 3.38 (m, 4H), 2.94 (br t, 2H), 2.43 (t, 2H), 2.14 (m, 2H), 1.84-1.87 (m, 8H) 1.42 (m, 2H) ppm 39
9-(4-(4-Amino-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 525.3; 0.48 min., LCMS method i ^1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, 1H), 7.41 (m, 1H), 7.30-7.15 (m, 1H), 6.91 (d, 1H), 6.05 (d, 1H), 4.47 (d, 2H), 4.13 (brs, 2H), 3.12 (dt, 2H), 2.87 (t, 2H), 2.42 (t, 2H), 2.05-2.11 (m, 4H), 1.79-1.88 (m, 3H), 1.4-1.52 (m, 4H) ppm 40
1-(3,4-Difluorophenyl)-9-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one 527.4; 0.65 min, LCMS method i ^1H NMR (300 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 6.91 (d, 1H), 4.42-4.62 (m, 4H), 3.12-2.78 (m, 3H), 2.42 (t, 2H), 2.20-2.02 (m, 2H), 1.92-1.79 (m, 4H), 1.62-1.75 (m, 4H), 1.32-1.54 (m, 4H). 41
9-(2-Amino-5-fluoro-6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 559.4; 0.58 min., LCMS method i ^1H NMR (300 MHz, DMSO-d6) δ 7.44 (m, 1H), 7.23 (m, 1H), 6.91 (d, 1H), 5.99 (s, 1H), 5.70 (s, 2H), 3.82-4.0 (m, 4H), 2.91-3.07 (m, 4H), 2.41 (t, 2H), 2.09 (m, 2H), 1.75-1.88 (m, 4H), 1.51-1.62 (m, 6H). 42
1-(3,4-Difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 526.3; 1.28 min., LCMS method j ^1H NMR (chloroform-d, 300 MHz) δ 8.3 (s, 1H), 7.25-7.1 (m, 1H), 6.94-6.9 (m, 1H), 6.8 (m, 1H), 4.26-4.23 (m, 2H), 3.70 (d, 2H), 3.25 (t, 2H), 2.99 (t, 2H), 2.62 (t, 2H), 2.1 (br, 2H), 1.98-1.88 (m, 4H), 1.79-1.7 (m, 4H), 1.32-1.25 (m, 2H). 43
9-(6-Amino-2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 459.3; 0.48 min., LCMS method i ^1H NMR (DMSO-d6, 300 MHz) δ 7.5-7.38 (m, 1H), 7.3-7.18 (m, 1H), 6.92 (br, 1H), 5.63 (brs, 2H), 5.5 (s, 1H), 4.81 (s, 1H), 4.09 (d, 2H), 3.64 (s, 4H), 2.79 (t, 2H), 2.41 (m, 2H), 2.08 (br, 2H), 1.81-1.77 (m, 4H), 1.5-1.35 (m, 4H) 44
1-(4-Chloro-3-fluorophenyl)-9-(6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 516.1; 0.66 min., LCMS method i ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1 H) 7.59 (t, J=8.44 Hz, 1 H) 7.24 (dd, J=10.27, 2.08 Hz, 1 H) 6.96 (d, J=8.65 Hz, 1 H) 5.70-5.76 (m, 1 H) 4.25 (br d, J=12.59 Hz, 2 H) 4.09 (br t, J=15.16 Hz, 4 H) 2.94 (br t, J=12.47 Hz, 2 H) 2.39-2.47 (m, 2 H) 1.93-2.19 (m, 2 H) 1.82-1.92 (m, 4 H) 1.48 (td, J=12.84, 4.28 Hz, 2 H) 45
9-(6-(1,4-Oxazepan-4-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 458.4; 0.47 min., LCMS method i ¹ H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.42 (dt, J=10.9, 8.8 Hz, 1H), 7.31-7.13 (m, 1H), 6.92 (dq, J=6.5, 2.3 Hz, 1H), 5.66 (s, 1H), 4.20 (d, J=13.4 Hz, 2H), 3.64 (t, J=9.5 Hz, 6H), 3.57-3.46 (m, 2H), 2.96-2.79 (m, 2H), 2.42 (t, J=6.7 Hz, 2H), 2.11 (s, 2H), 1.81 (td, J=12.3, 5.6 Hz, 6H), 1.50 (dd, J=14.4, 9.9 Hz, 2H). 46
rac -9-(2-Amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 471.3; 0.44 min., LCMS method i 1H NMR (DMSO-d6, 300 MHz) δ 7.47-7.38 (m, 1H), 7.28-7.2 (m, 1H), 6.94-6.88 (m, 1H), 5.55 (br, 2H), 4.95 (br, 1H), 4.73 (br, 1H), 4.57 (s, 1H), 4.12 (d, 2H), 3.7-3.52 (m, 2H), 3.25 (s, 1H), 3.17-3.09 (m, 1H), 2.78 (t, 2H), 2.41 (t, 2H), 2.07 (br, 2H), 1.9-1.75 (m, 5H), 1.5-1.38(m, 2H).

Example 47. 1-(3,4-Difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. (9-(6-Chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 4,6-dichloropyrimidine (0.188 g, 1.26 mmol) and 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one hydrochloride ( Intermediate A , 0.564, 1.26 mmol) in EtOH (2 mL) was treated with TEA (0.642 g, 1.50 mmol) and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated and the residue was partitioned between water and EtOAc. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give (9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.410 g, crude) in as a white solid. Mass/charge = 393.1 [M+H] ⁺ ; t _R = 1.43 min. (LCMS method j)

Step B. 1-(3,4-Difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of (9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.10 g, 0.25 mmol), 4-trifluoromethylpyrazole (0.041 g, 0.30 mmol) and Cs₂CO₃(0.165 g, 0.5 mmol) in DMF (1 mL) was heated at 120 °C for 12 h. The mixture was cooled to rt, partitioned between water and EtOAc. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. Purification by preparative HPLC (Waters Xbridge, 5 μm, 21.2 x 150 mm; eluting with water/ACN) gave the title compound (24 mg, 0.048 mmol) as an off-white solid.¹H NMR (400 MHz, methanol-d₄) δ 8.92 (s, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.24-7.31 (m, 1H), 7.16 (s, 1H), 7.08-7.14 (m 1H), 6.92 (d, 1H), 4.40 (brs, 2H), 3.16 (t, 2H), 2.58 (t, 2H), 2.27 (brs, 2H), 1.96-2.02 (m, 4H), 1.68-1.81 (m, 2H); mass/charge=493.2 [M+H]⁺;t_R=1.25 minutes (LCMS method j)

Using methods similar to those described for the preparation of Example 47 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 48
1-(3,4-Difluorophenyl)-9-(2-methyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 439.2; 1.53 min., LCMS method g ^1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.80 (s, 1H), 7.42 (m, 1H), 7.25 (m, 1H), 6.91 (d, 1H), 6.87 (s, 1H), 6.53 (s, 1H), 4.30 (brs, 2H), 3.06 (t, 3H), 2.40 (m, 3H), 2.15 (brs, 2H), 1.8-1.95 (m, 4H), 1.53 (t, 2H). 49
4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(1H-pyrazol-1-yl)pyrimidin-2-carbonitrile 450.2; 4.50 min., LCMS method f ^1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 1H), 7.89 (s, 1H), 7.42 (m, 1H), 7.30-7.17 (m, 1H), 7.72(s, 1H), 6.60 (dd, 1H), 3.41 (m, 2H), 3.30-3.07 (brs, 2H), 2.45 (t, 2H), 2.12-2.2 (m, 2H), 1.8-1.98 (m, 4H), 1.5-1.62 9 (m, 2H)

Example 50. 1-(3,4-Difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 4-Chloro-2-methoxy-6-(1H-pyrazol-1-yl)pyrimidine

A mixture of cesium carbonate (71.8 mg, 0.220 mmol), 1H-pyrazole (15 mg, 0.22 mmol), and 4,6-dichloro-2-methoxypyrimidine (39 mg, 0.22 mmol) in DMF (0.9 mL) was stirred at rt for 2 h. LCMS analysis indicated complete conversion of 4-chloro-2-methoxy-6-(1H-pyrazol-1-yl)pyrimidine, which was not isolated. m/z = 211.1 [M+H] ⁺ ; t _R = 0.93 min. (LCMS method e)

Step B. 1-(3,4-Difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

To the reaction mixture in step A was added 1-(3,4-difluorophenyl-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 62 mg, 0.22 mmol), DIEA (0.13 mL, 0.74 mmol). The mixture was heated at 50 °C overnight. After cooling to rt, the mixture was partitioned between EtOAc/heptane 2:1, washed with water (5x), brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (0-100% MeOH in EtOAc) followed by reversed phase chromatography (RediSep® Rf Gold® reversed phase C18 column, 50 g, 0-100% ACN in water) afforded the title compound (30 mg, 0.065 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J=2.7, 0.7 Hz, 1H), 7.81 (dd, J=1.6, 0.7 Hz, 1H), 7.42 (dt, J=10.7, 8.9 Hz, 1H), 7.25 (ddd, J=11.5, 7.4, 2.4 Hz, 1H), 6.93 (dtd, J=7.0, 2.5, 1.3 Hz, 1H), 6.73 (s, 1H), 6.54 (dd, J=2.7, 1.6 Hz, 1H), 4.14 (d, J=100.0 Hz, 2H), 3.83 (s, 3H), 3.09 (t, J=13.1 Hz, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.15 (s, 2H), 1.98-1.80 (m, 4H), 1.65-1.46 (m, 2H); m/z=455.3 [M+H] ⁺ ; t _R =1.01 minutes (LCMS method e).

Using methods similar to those described for the preparation of Example 50 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 51
9-(6-(1H-Pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 493.2; 1.19 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J=2.7, 0.7 Hz, 1H), 7.89 (dd, J=1.6, 0.7 Hz, 1H), 7.42 (dt, J=10.7, 8.9 Hz, 1H), 7.25 (ddd, J=11.6, 7.4, 2.4 Hz, 1H), 7.18 (s, 1H), 6.94 (ddd, J=8.7, 3.8, 1.8 Hz, 1H), 6.60 (dd, J=2.7, 1.6 Hz, 1H), 4.96-3.72 (m, 2H), 3.18 (s, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.16 (d, J=7.7 Hz, 2H), 2.01-1.91 (m, 2H), 1.86 (p, J=6.6 Hz, 2H), 1.72-1.50 (m, 2H). 52
1-(3,4-Difluorophenyl)-9-(2-morpholino-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 510.4; 1.08 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J=2.6, 0.7 Hz, 1H), 7.75 (dd, J=1.6, 0.7 Hz, 1H), 7.42 (dt, J=10.6, 8.9 Hz, 1H), 7.24 (ddd, J=11.6, 7.4, 2.4 Hz, 1H), 6.93 (ddd, J=9.6, 4.5, 2.4 Hz, 1H), 6.49 (dd, J=2.6, 1.6 Hz, 1H), 6.43 (s, 1H), 4.23 (s, 2H), 3.71-3.58 (m, 8H), 3.02 (t, J=13.1 Hz, 2H), 2.43 (t, J=6.7 Hz, 2H), 2.13 (s, 2H), 1.99-1.75 (m, 4H), 1.62-1.45 (m, 2H). 53
1-(3,4-Difluorophenyl)-9-(2-(dimethylamino)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 468.4; 1.18 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J=2.6, 0.8 Hz, 1H), 7.74 (dd, J=1.6, 0.7 Hz, 1H), 7.42 (dt, J=10.7, 8.9 Hz, 1H), 7.24 (ddd, J=11.6, 7.4, 2.4 Hz, 1H), 6.99-6.88 (m, 1H), 6.49 (dd, J=2.6, 1.6 Hz, 1H), 6.37 (s, 1H), 4.24 (s, 2H), 3.07 (s, 6H), 3.00 (d, J=13.1 Hz, 2H), 2.43 (t, J=6.7 Hz, 2H), 2.14 (s, 2H), 1.96-1.75 (m, 4H), 1.54 (d, J=13.8 Hz, 2H). 54
9-(6-(1H-1,2,4-Triazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 426.2; 0.80 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.43 (d, J=0.9 Hz, 1H), 8.31 (s, 1H), 7.42 (dt, J=10.7, 8.9 Hz, 1H), 7.25 (ddd, J=11.6, 7.5, 2.5 Hz, 1H), 7.00 (d, J=1.1 Hz, 1H), 6.93 (ddt, J=8.6, 3.9, 1.9 Hz, 1H), 4.09 (d, J=5.3 Hz, 2H), 3.12 (t, J=13.2 Hz, 2H), 2.44 (t, J=6.7 Hz, 2H), 2.16 (s, 2H), 2.00-1.78 (m, 4H), 1.67-1.46 (m, 2H). 55
9-(6-(4-Chloro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 459.2; 1.15 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=0.8 Hz, 1H), 8.38 (d, J=0.9 Hz, 1H), 7.98 (d, J=0.8 Hz, 1H), 7.41 (dt, J=10.7, 8.9 Hz, 1H), 7.24 (ddd, J=11.6, 7.5, 2.5 Hz, 1H), 7.01 (d, J=1.0 Hz, 1H), 6.97-6.85 (m, 1H), 3.38 (s, 2H), 3.10 (t, J=13.1 Hz, 2H), 2.43 (t, J=6.7 Hz, 2H), 2.15 (s, 2H), 2.00-1.75 (m, 4H), 1.55 (td, J=12.9, 4.7 Hz, 2H). 56
9-(6-(4-Fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 443.2; 1.06 min., LCMS method e ¹ H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J=4.5, 0.9 Hz, 1H), 8.37 (d, J=0.9 Hz, 1H), 7.96 (dd, J=4.3, 0.9 Hz, 1H), 7.41 (dt, J=10.7, 8.9 Hz, 1H), 7.24 (ddd, J=11.6, 7.5, 2.5 Hz, 1H), 7.01 (d, J=1.0 Hz, 1H), 6.93 (ddt, J=8.7, 3.8, 1.6 Hz, 1H), 4.30 (s, 2H), 3.10 (t, J=13.1 Hz, 2H), 2.43 (t, J=6.8 Hz, 2H), 2.15 (s, 2H), 1.97-1.75 (m, 4H), 1.55 (td, J=13.1, 12.4, 4.3 Hz, 2H). 57
1-(3,4-Difluorophenyl)-9-(6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 493.1; 1.60 min., LCMS method f ^1H NMR (400 MHz, methanol- _d4 ) δ 8.65-8.64 (m, 1H), 8.37 (s, 1H), 7.32-7.25 (m, 1H), 7.14-7.08 (m, 2H), 6.93-6.91 (m, 1H), 6.82 (m, 1H), 4.45 (brs, 2H), 3.16 (t, 2H), 2.58 (t, 2H), 2.27 (br, 2H), 2.03-1.96 (m, 4H), 1.82-1.7 (m, 2H). 58
1-(3,4-Difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 492.9; 0.65 min, LCMS method i ^1H NMR (400 MHz, chloroform-d) δ 8.44 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.21-7.12 (m, 1H), 6.92-6.86 (m, 1H), 6.82-6.74 (m, 1H), 6.35 (s, 1H), 4.45 (brs, 2H), 3.1 (t, 2H), 2.64-2.62 (m, 2H), 2.2-2.17 (m, 2H), 1.99-1.81 (m, 6H). 59
9-(2-Amino-5-fluoro-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 458.3; 0.58 min., LCMS method i 1H NMR (DMSO-d6, 300 MHz) δ 8.21 (d, 1H), 7.76 (s, 1H), 7.5-7.39 (m, 1H), 7.3-7.2 (m, 1H), 6.96-6.9 (m, 1H), 6.5-6.49 (m, 1H), 6.32 (s, 2H), 4.2 (d, 2H), 3.12 (t, 2H), 2.42 (t, 2H), 2.2-2.1 (m, 2H), 1.89-1.84 (m, 4H), 1.68-1.52 (m, 2H). 60
9-(4-Amino-6-(4-fluoro-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 459.3; 0.65 min., LCMS method l ^1H NMR (chloroform-d, 300 MHz) δ 8.25 (d, 1H), 7.63 (d, 1H), 7.2-7.12 (m, 1H), 6.9-6.84 (m, 1H), 6.8-6.72 (m, 1H), 5.3 (br, 2H), 4.8 (br, 2H), 3.05-2.9 (m, 2H), 2.62 (t, 2H), 2.2-2.12 (br, 2H), 1.97-1.92 (m, 2H), 1.81-1.7 (m, 4H). 61
1-(3,4-Difluorophenyl)-9-(6-(oxetan-3-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 499.3; 1.11 min., LCMS method e ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.29 (dt, J=10.5, 8.8 Hz, 1H), 7.16-7.05 (m, 1H), 6.92 (ddt, J=8.3, 3.9, 2.0 Hz, 1H), 6.11 (s, 1H), 5.57 (p, J=5.7 Hz, 1H), 4.92 (t, J=6.9 Hz, 2H), 4.63 (dd, J=7.6, 5.1 Hz, 2H), 4.29 (s, 2H), 3.10 (td, J=13.3, 2.8 Hz, 2H), 2.58 (t, J=6.8 Hz, 2H), 2.35-2.16 (m, 2H), 1.97 (td, J=13.3, 7.6 Hz, 4H), 1.73 (s, 2H).

Example 62 1-(3,4-Difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 9-(6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.15 g, 0.38 mmol) in DMF (2 mL) was flushed with argon gas and treated with 2-(tributylstannyl)oxazole (0.273 g, 0.76 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.11 mmol). The reaction mixture was heated to 100 °C for 16 h. The reaction mixture was cooled to rt, diluted with water, and extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Purification by preparative HPLC (LUNA 5.0 μm, 21.2 x 250 mm; eluting with 0.1% aqueous HCOOH:ACN) afforded the title compound (44 mg) as an off-white solid.¹H NMR (chloroform-d, 600 MHz) δ 8.64 (s, 1H), 7.81 (s, 1H), 7.29 (m, 1H), 7.25-7.24 (m, 1H), 7.25-7.14 (m, 1H), 6.89-6.88 (m, 1H), 6.78-6.77 (m, 1H), 4.41 (brs, 2H), 3.1 (t, 2H), 2.63-2.62 (m, 2H), 2.17 (m, 2H), 2.00-1.94 (m, 2H), 1.87-1.78 (m, 4H); mass/charge=426.2 [M+H]⁺;t_R=1.33 minutes (LCMS method j).

Example 63. 9-(6-Amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 6-Chloro-2-(pyridin-2-yl)pyrimidin-4-amine

A suspension of 4,6-dichloro-2-(pyridin-2-yl)pyrimidine (112 mg, 0.495 mmol) in isopropanol (0.5 mL) and ammonium hydroxide (33%, 0.5 mL, 4.24 mmol) was stirred at 50 °C. After 3 h, an additional portion of ammonium hydroxide solution (0.25 mL) was added and stirring was continued for 3 h. The solution was cooled to rt, diluted with saturated sodium bicarbonate solution and extracted with DCM. The organic extracts were dried over magnesium sulfate and concentrated to give 6-chloro-2-(pyridin-2-yl)pyrimidin-4-amine (85 mg, 0.41 mmol) as a sand-colored solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.68 (ddd, J=4.7, 1.8, 0.9 Hz, 1H), 8.21 (dt, J=8.0, 1.1 Hz, 1H), 7.93 (td, J=7.7, 1.8 Hz, 1H), 7.50 (ddd, J=7.5, 4.7, 1.2 Hz, 1H), 7.40 (s, 2H), 6.48 (s, 1H); m/z=207.1 [M+H] ⁺ ; t _R =0.48 min (LCMS method e).

Step B. 9-(6-Amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 56 mg, 0.20 mmol), 6-chloro-2-(pyridin-2-yl)pyrimidin-4-amine (41 mg, 0.20 mmol) and DIEA (104 μL, 0.595 mmol) in DMF (0.7 mL) was heated at 100 °C overnight. After cooling to rt, the mixture was diluted with DCM and washed with water then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0-100% MeOH in EtOAc) followed by reversed-phase chromatography (RediSep® Rf Gold® reversed-phase C18 column, 50 g, 0-100% ACN in water) gave the title compound (16 mg, 0.034 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ 8.61 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.23-8.08 (m, 1H), 7.83 (td, J=7.7, 1.8 Hz, 1H), 7.51-7.34 (m, 2H), 7.25 (ddd, J=11.5, 7.5, 2.4 Hz, 1H), 7.00-6.88 (m, 1H), 6.32 (s, 2H), 5.56 (s, 1H), 4.18 (s, 2H), 2.95 (t, J=12.9 Hz, 2H), 2.43 (t, J=6.8 Hz, 2H), 2.13 (s, 2H), 1.88 (t, J=9.5 Hz, 4H), 1.55 (t, J=11.1 Hz, 2H); mass/charge=451.3 [M+H] ⁺ ; t _R =1.29 minutes (LCMS method e).

Example 64. 9-(2-Amino-6-(4-(trifluoromethyl)-1 H -pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 4-Chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-amine

A mixture of 4-(trifluoromethyl)-1H - pyrazole (0.183 g, 1.35 mmol), 2-amino-4,6-dichloropyrimidine (0.200 g, 1.23 mmol) and _Cs2CO3 (0.799 g, 2.45 mmol) in dioxane (4 mL) was stirred at 100 °C for 12 h. After cooling to rt, the reaction mixture _was diluted with water and extracted with EtOAc. _The extracts were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure to give 4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-amine as a white solid. The crude product was carried on to the next step without purification. Mass/charge=264.0 [M+H] ⁺

Step B. 9-(2-Amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.150 g, 0.535 mmol), 4-chloro-6-(4-trifluoromethyl)-1H pyrazol-1-yl)pyrimidin-2-amine (0.197 g, 0.749 mmol) and DIPEA (0.28 mL, 1.61 mmol) in EtOH (3 mL) were stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (KINETEX EVO C18, 5 μm, 21.2 × 150 mm; elution with water:ACN) afforded the title compound (97 mg, 0.19 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.21 (s, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.41 (d, 3H), 4.24 (m, 2H), 3.01 (t, 2H), 2.42 (t, 2H), 2.13 (d, 2H), 1.85 (m, 4H), 1.50 (m, 2H); mass/charge=508.15 [M+H]⁺;t_R=1.50 minutes (LCMS method j)

Example 65. 1-(3,4-Difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one

Step A. Methyl 4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxylate

A mixture of methyl 4,6-dichloropyrimidine-2-carboxylate (0.500 g, 2.66 mmol), 4-(trifluoromethyl)-1H- _pyrazole (0.360 g, 2.66 mmol) and _Cs2CO3 (1.70 g, 5.31 mmol) in dioxane (5 mL) was stirred at rt for three hours. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure to give methyl 4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate as a white solid (0.550 _g ). The crude product was used without further purification.

Step B. Methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxylate.

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.370 g, 1.35 mmol), methyl 4-chloro-6-(4-trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate (0.550 g, 1.79 mmol) and DIPEA (0.700 g, 5.37 mmol) in EtOH (5 mL) were heated at 80 °C for two hours. The mixture was diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate (0.350 g, 0.636 mmol) as a white solid. W/Z=551.2 [M+H]⁺

Step C. 1-(3,4-Difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one.

Methylmagnesium bromide (3.0 M solution in diethyl ether, 0.034 mL, 0.10 mmol) was added to a stirred solution of methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate (0.050 g, 0.034 mmol) in THF (2 mL) cooled to 0 °C. The reaction mixture was then stirred at rt for three hours. The reaction mixture was quenched with aqueous NH₄Cl and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (LUNA Phenomenex, 5 μm, 21.2 × 250 mm; elution with 0.02% NH₄OH to H₂O:ACN) gave the title compound (3 mg, 0.006 mmol) as a white solid.¹H NMR (300 MHz, methanol-d₄) δ 9.16 (s, 1H), 8.02 (s, 1H), 7.23-7.28 (m, 1H), 7.07-7.14 (m, 1H), 7.04 (s, 1H), 6.90-6.94 (m, 1H), 4.45 (brs, 2H), 3.16 (t, 2H), 2.58 (t, 2H), 2.19-2.35 (m, 2H), 1.88-2.09 (m, 4H), 1.76 (brs, 2H), 1.51 (s, 6H); mass/charge=551.2 [M+H]⁺;t_R=1.80 minutes (LCMS method l).

Example 66. Synthesis of 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one

Step A. 1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one.

To a stirred solution of methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate (1.100 g, 1.998 mmol) in MeOH (15 mL) cooled to 0 °C was added NaBH ₄ (0.230 g, 5.99 mmol) portionwise. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Triturating the resulting solid with pentane gave the title compound. (0.950 g, 1.82 mmol) as an off-white solid. ¹ H NMR (300 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.30 (s, 1H), 7.42 (m, 1H), 7.25 (m, 1H), 6.9-6.96 (m, 2H), 4.97 (t, 1H), 4.37 (d, 2H), 3.10-3.18 (m, 2H), 2.40-2.45 (m, 2H), 2.1-2.2 (m, 2H), 1.8-1.98 (m, 4H), 1.49-1.6 (m, 2H) (2 aliphatic protons merged with DMSO peak); m/z=523.2 [M+H] ⁺ ; t _R =1.64 minutes (LCMS method l)

Example 67. rac -1-(3,4-Difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one

Step A. 4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carbaldehyde(1p).

MnO₂(0.230 g, 2.6 mmol) was added to a stirred solution of 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one (0.020 g, 0.038 mmol) in DCM (5 mL) cooled to 0 °C. The reaction mixture was stirred at rt for 12 h. The reaction mixture was poured into water and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product as a yellow gummy solid (0.025 g), which was carried forward without purification. Mass/charge=523.2 [M+H]⁺

Stage B. rac -1-(3,4-Difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one.

MeMgBr (3.0 M in diethyl ether, 170 µL, 0.52 mmol) was added to a stirred solution of 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carbaldehyde (0.080 g, 0.172 mmol) in THF (2 mL) cooled to 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with aqueous NH₄Cl and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (LUNA Phenomenex, 5 μm, 21.2 × 250 mm; elution with 0.02% NH₄OH in a mixture of H₂O:ACN) gave the title compound (2 mg, 0.004 mmol) as an off-white solid.¹H NMR (300 MHz, methanol-d₄) δ 9.13 (s, 1H), 8.02 (s, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 7.04 (s, 1H), 6.92 (m, 1H), 4.65 (q, 1H), 4.46 (s, 2H), 3.15 (m, 2H), 2.58 (t, 2H), 2.27 (d, 2H), 1.98 (dd, 4H), 1.75 (s, 2H), 1.46 (d, 3H); mass/charge=537.3 [M+H]⁺;t_R=1.74 minutes (LCMS method l).

Example 68. 4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide

Step A. 4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide.

Ammonia (2.0 M in ethanol, 3 mL) was added to methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(4-chloro-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine-2-carboxylate (0.085 g, 0.15 mmol) and the mixture was heated at 50°C for 4 h. The mixture was concentrated under reduced pressure. Purification by preparative HPLC (Waters Xbridge, 5 μm, 21.2×150 mm; elution with 0.02% NH₃in a mixture of H₂O:ACN) gave the title compound (0.028 g, 0.052 mmol) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 7.74 (s, 1H), 7.41 (m, 1H), 7.2-7.3 (m, 1H), 7.13 (s, 1H), 6.9-6.94 (m, 1H), 3.14 (s, 2H), 2.44 (t, 3H), 2.17 (m, 2H), 2.00-1.86 (m, 4H), 1.56 (t, 2H); mass/charge=536.4 [M+H]⁺;t_R=1.47 minutes (LCMS method l)

Example 69. 9-(2-Chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step-A. 2,4-Dichloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine

A mixture of 2,4,6-trichloropyrimidine (0.50 g, 2.7 mmol), 4-(trifluoromethyl)-1H-pyrazole (0.27 g, _2.0 mmol) and _Cs2CO3 (1.70 g, 5.45 mmol) in dioxane (5 mL) was stirred at rt for 3 h. The reaction mixture was diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over _Na2SO4 , _filtered and concentrated under reduced pressure to give the crude product (0.20 g), which was used for the next step without further purification.

Step B. 9-(2-Chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2,4-dichloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidine (0.20 g, 0.71 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.197 g, 0.706 mmol) and DIPEA (0.27 mL, 2.1 mmol) in EtOH (3 mL) was heated at 80 °C for 2 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by preparative HPLC (YMC-ACTUS TRIART, 5.0 μm, 20 x 150 mm; elution with 0.02% NH ₄ OH in water:ACN) gave the title compound (85 mg, 0.16 mmol). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.20 (s, 1H), 7.41 (m, 1H), 7.25 (m, 1H), 6.99-6.83 (m, 2H), 4.82 (s, 1H), 3.96 (s, 1H), 3.10 (brs, 2H), 2.42 (t, 2H), 2.14 (d, 2H), 2.01-1.72 (m, 4H), 1.53 (m, 2H); m/z=527.1 [M+H] ⁺ ; t _R =1.74 min (LCMS method l).

Using methods similar to those described for the preparation of Example 69 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 70
(R)-9-(2-Chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 479.2; 1.47 min., LCMS method j ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.43 (m, 1H), 7.25 (m, 1H), 6.92 (m, 1H), 6.54 (s, 1H), 5.32 (t, 1H), 3.66-3.86 (m, 4H), 3.03 (t, 2H), 3.21-3.13 (m, 1H), 2.42 (t, 2H), 2.25-2.02 (m, 3H), 1.71-1.98 (m, 5H), 1.46-1.52 (m, 2H) 71
(S)-9-(2-Chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 479.2; 1.47 min., LCMS method j ^1H NMR (DMSO- _d6 , 300 MHz) δ 7.46-7.38 (m, 1H), 7.24-7.2 (m, 1H), 6.84 (m, 1H), 6.52 (s, 1H), 5.32-5.28 (m, 1H), 4.5-3.62 (m, 6H), 3.0 (br, 2H), 2.42-2.39 (m, 2H), 2.18-2.07 (m, 3H), 1.92-1.74 (m, 5H), 1.52-1.4 (m, 2H). 72
(R)-9-(4-Chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 479.4; 1.74 min., LCMS method l ^1H NMR (DMSO- _d6 , 300 MHz) δ 7.44-7.3 (m, 1H), 7.24-7.18 (m, 1H), 6.92-6.88 (m, 1H), 6.08 (s, 1H), 5.4 (m, 1H), 4.42-4.32 (m, 2H), 3.88-3.62 (m, 4H), 3.0 (t, 2H), 2.42-2.40 (m, 3H), 2.25-2.08 (m, 3H), 1.88-1.84 (m, 4H), 1.51-1.4 (m, 2H).

Example 73. 1-(3,4-Difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2,4-Dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine

Mixture 2,4,6-trichloropyrimidine (0.200 g, 1.09 mmol), Cs₂CO₃(1.42 g, 2.18 mmol) and 4-fluoro-1H-pyrazole (0.18 g, 2.2 mmol) in dioxane (6 mL) were stirred at rt for 12 h. The reaction mixture was diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative TLC eluting with 1:1 EtOAc/hexane afforded 2,4-dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine as an off-white solid (60 mg, 0.26 mmol); m/z=233.0, [M+H]⁺

Step B. 9-(2-Chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 2,4-dichloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidine (60 mg, 0.26 mmol) in EtOH (5 mL) was treated with 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 72 mg, 0.26 mmol) and DIPEA (0.10 mL, 0.77 mmol) and heated at 80 °C for 2 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude solid was washed with pentane to give 9-(2-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (110 mg, 0.231 mmol) as an off-white solid. W/Z = 476.9 [M+H] ⁺

Stage-C. 1-(3,4-Difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of 9-(2-chloro-6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (100 mg, 0.209 mmol) in n-butanol (2 mL) was treated with morpholine (91 mg, 1.0 mmol) and DIPEA (80 μL, 0.45 mmol) and the reaction mixture was heated at 120 °C for 12 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude solid was washed with pentane to give the title compound (34 mg, 0.064 mmol) as a brown solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.60 (dd, 1H), 7.76 (dd, 1H), 7.39-7.45 (m, 1H), 7.1-7.26 (m, 1H), 6.92-6.94 (m, 1H), 5.76 (s, 1H), 4.33 (brs, 2H), 3.63 (m, 4H), 3.53 (m, 4H), 2.96 (t, 2H), 2.43 (t, 2H), 2.14 (brs, 2H), 1.95-1.78 (m, 3H), 1.50 (m, 2H); mass/charge=528.3 [M+H] ⁺ ; t _R =1.37 minutes (LCMS method k).

Example 74. 9-(2-Amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 9-(2-Amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.513 g, 1.83 mmol), 2-amino-4,6-dichloropyrimidine (0.300 g, 1.83 mmol), and DIPEA (0.64 mL, 3.7 mmol) in EtOH (7 mL) was heated at 80 °C for 12 h. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (2-5% MeOH in DCM) gave 9-(2-amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.520 g, 1.27 mmol) as a white solid. W/Z = 410.3 [M+2]

Step B. 9-(2-Amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

9-(2-Amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.300 g, 0.735 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl))-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.540 g, 2.21 mmol) was stirred in DME (6 mL) and H₂O (2 ml) at RT with argon purging for 10 min. K₂CO₃(0.304 g, 2.21 mmol) was added to the reaction mixture with argon flush followed by addition of Pd(dppf)Cl₂·DCM (0.120 g, 0.147 mmol). The mixture was heated at 100 °C for 16 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (Waters Xbridge, 5 μm, 21.2 × 150 mm; elution with 0.02% NH₄OH in a mixture of H₂O:ACN) gave the title compound (17 mg, 0.035 mmol) as a white solid.¹H NMR (300 MHz, chloroform-d ) δ 7.17 (m, 1H), 6.72-6.92 (m, 2H), 6.53 (s, 1H), 5.88 (s, 1H), 4.68 (s, 2H), 4.26 (d, 2H), 3.53 (brs, 2H), 2.90-2.96 (m, 2H), 2.59-2.81 (m, 6H), 2.1-2.22 (m, 2H), 1.92-1.96 (m, 2H), 1.74-1.92 (m, 2H); m/z=490.25 [M+H]⁺;t_R=1.32 minutes (LCMS method j)

Example 75. 9-(2-Amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

9-(2-Amino-6-chloropyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.100 g, 0.245 mmol) and 4-Fluorophenylboronic acid (0.068 g, 0.49 mmol) was stirred in DME (0.9 mL) and H₂O (2.1 ml) at RT with argon purging for 10 min. K₂CO₃(0.101 g, 0.735 mmol) was added to the reaction mixture with argon flushing followed by the addition of Pd(dppf)Cl₂·DCM (0.035 g, 0.049 mmol). The mixture was heated at 90 °C for 16 h. After cooling to rt, water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (Gemini, 5 μm, 21.2 × 250 mm; elution with 0.02% NH₄OH in a mixture of H₂O:ACN) gave the title compound (50 mg, 0.11 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (m, 2H), 7.36-7.48 (m, 1H), 7.21-7.35 (m, 3H), 6.9-6.94 (m, 1H), 6.92 6.49 (s, 1H), 6.05 (s, 2H), 4.3-4.62 (m, 2H), 2.93 (t, 2H), 2.41-2.43 (m, 2H), 2.07-2.15 (m, 2H), 1.79-1.93 (m, 4H), 1.57-1.35 (m, 2H); mass/charge=468.25 [M+H]⁺;t_R=1.30 minutes (LCMS method j)

Example 76. 9-(2-Amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 50 mg, 0.18 mmol), 4-chloro-6-(trifluoromethyl)pyrimidin-2-amine (49 mg, 0.25 mmol), and cesium carbonate (106 mg, 0.325 mmol) in DMF (0.7 mL) was heated at 50 °C for three hours. The reaction mixture was cooled to rt, diluted with water, extracted with DCM, dried over magnesium sulfate, and concentrated. Purification by reverse phase chromatography (RediSep® Rf Gold® reverse phase C18 column, 50 g, 0-100% ACN in water) gave the title compound (55 mg, 0.125 mmol) as a white solid. 1H NMR (400 MHz) δ 7.38-7.22 (m, 1H), 7.17-7.03 (m, 1H), 6.98-6.85 (m, 1H), 6.65 (s, 1H), 4.43 (s, 2H), 3.20 (t, J=13.6 Hz, 2H), 2.58 (t, J=6.9 Hz, 2H), 2.26 (d, J=7.8 Hz, 2H), 2.10-1.89 (m, 4H), 1.75 (s, 2H); m/z=242.3 [M+H] ⁺ ; t _R =0.88 min (LCMS method h)

Example 77. 9-(2-Amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-Amino-6-(perfluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (3.00 g, 12.8 mmol), guanidine hydrochloride (3.65 g, 38.4 mmol), and NaOMe (1.30 g, 24.0 mmol) in MeOH (10 mL) was stirred at 80 °C for 12 h. The reaction mixture was added water and extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 2-amino-6-(perfluoroethyl)pyrimidin-4-ol as a gummy brown mass (2.645 g). The crude product was carried on without further purification. m/z = 230.2 [M+H] ⁺

Step B. 4-Chloro-6-(perfluoroethyl)pyrimidin-2-amine

A mixture of POCl ₃ (39 mL, 30 v) and 2-amino-6-(perfluoroethyl)pyrimidin-4-ol (1.30 g, 5.67 mmol) was heated under reflux at 100 °C for 12 h. After cooling to rt, aqueous NaHCO ₃ solution was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (8-12% EtOAc in hexanes) gave 4-chloro-6-(perfluoroethyl)pyrimidin-2-amine (0.180 g, 0.728 mmol) as a yellow liquid. m/z = 248.1 [M+H] ⁺

Step C. 9-(2-Amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

4-chloro-6-(perfluoroethyl)pyrimidin-2-amine mixture (0.180 g, 0.725 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.163 g, 0.581 mmol) and DIPEA (0.38 mL, 2.2 mmol) in EtOH (5 mL) were stirred at 80 °C for 12 h. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was carried out by preparative HPLC (Waters Xbridge, 5 μm, 20 × 150 mm; elution with 0.02% NH₄OH in a mixture of H₂O:ACN) gave the title compound (16 mg, 0.033 mmol) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (m, 1H), 7.24 (m, 1H), 6.97-6.84 (m, 1H), 6.55 (s, 2H), 6.33 (s, 1H), 2.97 (m, 2H), 2.42 (t, 4H), 2.12 (m, 2H), 1.86 (d, 4H), 1.49 (m, 2H); mass/charge=492.4 [M+H]⁺;t_R=2.12 minutes (LCMS method l)

Example 78

Step A. Ethyl 4,4,5,5-tetrafluoro-3-oxopentanoate

NaH (1.125 g, 46.88 mmol) was added to a stirred solution of methyl 2,2,3,3-tetrafluoropropanoate (2.50 g, 15.6 mmol) in EtOAc (10 mL). The reaction mixture was heated under reflux at 70 °C for 12 h. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product as a yellow liquid (4.361 g). The crude product was carried on to the next step without purification. m/z = 215.1 [M+H] ⁺

Step B. 2-Amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4,5,5-tetrafluoro-3-oxopentanoate (2.00 g, 9.24 mmol), guanidine hydrochloride (2.638 g, 27.77 mmol), and NaOMe (0.749 g, 13.9 mmol) in MeOH (20 mL) was stirred at 80 °C for 12 h. Water was added to the reaction mixture, and it was extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Washing the resulting solids with pentane and EtOAc gave 2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol (0.728 g, 3.45 mmol) as a yellow solid. Mass/charge=212.05 [M+H] ⁺

Step C. 9-(2-Amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Mixture of 2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-ol (0.200 g, 0.947 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.265 g, 0.947 mmol), PyBrop (0.485 g, 1.04 mmol) and TEA (0.40 mL, 2.8 mmol) in MeCN (4 mL) were heated at 80°C for 24 h. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with EtOAc) afforded the title compound as a pale yellow solid (0.231 g, 0.489 mmol).¹H NMR (400 MHz, DMSO-d₆) δ 7.41 (m, 1H), 7.23 (m, 1H), 6.90-6.92 (m, 1H), 6.42-6.7 (m, 3H), 6.27 (s, 1H), 4.25 (brs, 2H), 2.97 (t, 2H), 2.42 (t, 2H), 2.19-2.05 (m, 2H), 1.93-1.75 (m, 4H), 1.58-1.38 (m, 2H); mass/charge=474.2 [M+H]⁺;t_R=1.28 minutes (LCMS method j)

Example 79. 1-(3,4-Difluorophenyl)-9-(2-(hydroxyethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2-(Chloromethyl)-6-(perfluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (5.0 g, 21 mmol), 2-chloroacetimidamide hydrochloride (5.89 g, 45.7 mmol), and NaOMe (1.73 g, 32.0 mmol) in MeOH (20 mL) was stirred at 80 °C for 12 h. The reaction mixture was added water and extracted with EtOAc. The extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (35-40% EtOAc in hexanes) gave 2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-ol as an orange solid (0.254 g, 0.977 mmol). Mass/charge=260.95, [M+H] ⁺

Step B. 9-(2-(Chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-ol (0.100 g, 0.381 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.106 g, 0.381 mmol), PyBrop (0.266 g, 0.571 mmol) and TEA (0.16 mL, 1.1 mmol) in dioxane (5 mL) were stirred at rt for 12 h. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative TLC eluting with EtOAc afforded 9-(2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one as a yellow solid (0.091 g, 1.91 mmol). m/z=525.1 [M+H]⁺

Step C. (4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methyl acetate

KOAc (0.044 g, 0.458 mmol) was added to a stirred solution of 9-(2-(chloromethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.080 g, 0.152 mmol) in DMF (4 mL). The reaction mixture was stirred at rt for 12 h. Cold water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give (4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methyl acetate (0.045 g, 0.082 mmol) as a sticky yellow solid, which was carried on to the next step without purification. m/z=549.1 [M+H]⁺;t_R=1.55 min. (LCMS method j).

Step D. 1-(3,4-Difluorophenyl)-9-(2-(hydroxyethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

NaOMe (6 mg, 0.116 mmol) was added to a stirred solution of (4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(perfluoroethyl)pyrimidin-2-yl)methyl acetate (0.080 g, 0.15 mmol) in MeOH (4 mL). The reaction mixture was stirred at rt for 12 h. Water was added to the reaction mixture and it was extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative TLC eluting with EtOAc afforded the title compound (19 mg, 0.038 mmol) as an off-white solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.40 (m, 1H), 7.24 (m, 1H), 7.02 (s, 1H), 6.89-6.92 (m, 1H), 5.02 (t, 1H), 4.33 (d, 2H), 3.06 (brs, 2H), 2.41 (t, 2H), 2.10 (d, 2H), 1.97-1.74 (m, 4H), 1.4-1.58 (m, 2H); mass/charge=507.1 [M+H]⁺;t_R=1.48 minutes (LCMS method j).

Example 80. 1-(3,4-Difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2,4-Dichloro-6-(trifluoromethyl)pyrimidine

A mixture of 6-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione (5.00 g, 27.7 mmol), N,N-dimethylaniline (0.260 g, 25.0 mmol), and _POCl3 (15.7 g, 103 mmol) in MeCN (25 mL) was heated at 80 °C for 6 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with EtOAc twice. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give crude 2,4-dichloro-6-(trifluoromethyl)pyrimidine as _a brown oil (6.0 g), which was used in the next step without further purification.

Step B. 9-(2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 1.50 g, 5.35 mmol), 2,4-dichloro-6-(trifluoromethyl)pyrimidine (1.16 g, 5.35 mmol) and DIPEA (2.8 mL, 16 mmol) in EtOH (20 mL) was heated at 80 °C for 16 h. After cooling to rt, the reaction mixture was diluted with water and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (4-12% MeOH in DCM) gave 9-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one as an off-white solid (1.37 g). m/z=461.00 [M+H] ⁺

Step C. 9-(2-((Benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

To a stirred solution of 9-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.65 g, 1.4 mmol) in dioxane (4 mL) and water (4 mL) were added potassium benzyloxymethyl trifluoroborate (0.97 g, 4.2 mmol) and Cs ₂ CO ₃ (1.4 g, 4.2 mmol). The reaction mixture was purged with argon for 5 min. CataCXium-A® (0.10 g, 0.28 mmol) and Pd(OAc) ₂ (0.032 g, 0.14 mmol) were added and purging with argon was continued for 5 min. The reaction mixture was heated at 120 °C for 18 h. The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (12-65% EtOAc in hexanes) gave 9-(2-((benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (1.36 g). m/z = 547.2 [M+H] ⁺

Step D. 1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 9-(2-((benzyloxy)methyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (1.36 g) and Pd(OH) ₂ (2.72 g) in EtOH (40 mL) was placed under hydrogen atmosphere (1 atm, balloon) for 18 h. The reaction mixture was purged with nitrogen, filtered through a pad of celite, washed with EtOAc, and the clear filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (4-12% MeOH in DCM) gave 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one as an off-white solid (0.61 g, 1.1 mmol). m/z=547.1 [M+H] ⁺

Step E. 4-(1-(3,4-Difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylic acid

Jones reagent (1.8 mL) was added to a stirred solution of 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (0.33 g, 0.72 mmol) in acetone (7 mL). The reaction mixture was stirred at rt for 2 h followed by the addition of isopropanol (1.5 mL). The reaction mixture was diluted with water and extracted with EtOAc twice. The combined organic extracts _were washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure to give crude 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylic acid (0.230 g, 0.489 mmol), which was used for the next step without purification.

Step F. Ethyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylate

A mixture of 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylic acid (0.230 g, 0.489 mmol), _Cs2CO3 ( _0.160 g, 0.489 mmol) and ethyl iodide (0.060 mL, 0.73 mmol) in DMF (6 mL) was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give ethyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylate as a gummy brown liquid (0.21 g, 0.42 mmol). m/z = 499.1 [M+H] ⁺

Step G. 1-(3,4-Difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of ethyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(trifluoromethyl)pyrimidine-2-carboxylate (0.21 g, 0.42 mmol) in THF (10 mL) was cooled to 0 °C and treated with MeMgBr (3.0 M in ether, 4 mL, 12 mmol). The reaction temperature was raised to rt and stirring was continued for 18 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc twice. The combined extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Preparative HPLC (LUNA OMEGA, 5.0 μm, 21.2 x 250 mm; eluting with water/ACN) afforded the title compound as an off-white solid (5 mg, 0.010 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.28-7.45 (m, 1H), 7.23-7.27 (m, 1H), 7.03 (s, 1H), 6.93 (d, 1H), 3.07 (brs, 2H), 2.43 (t, 2H), 2.14 (brs, 2H), 1.84-1.93 (m, 4H), 1.5-1.62 (m, 2H), 1.37 (s, 6H). 2 protons are blocked by DMSO peak; m/z=485.2 [M+H] ⁺ ; t _R =1.54 minutes (LCMS method j).

Example 81

Step A. 2-Bromo-4-(2,2,2-trifluoroethoxy)pyridine

A solution of NaOtBu (0.529 g, 5.50 mmol) in DMSO (3 mL) was added dropwise to a solution of 2-bromo-4-fluoropyridine (0.52 mL, 5 mmol) and 2,2,2-trifluoroethanol (0.54 mL, 7.5 mmol) in 1 mL DMSO. The reaction mixture was stirred for 2 h at rt, quenched with ice water and extracted with DCM. The combined organic extracts were carefully evaporated (the product is volatile). The crude product was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to give 2-bromo-4-(2,2,2-trifluoroethoxy)pyridine (1.02 g, 3.78 mmol) as a colorless liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.28 (d, 1H), 7.45 (d, 1H), 7.19 (dd, 1H), 4.97 (q, 2H) ppm; m/z=256.1 [M+H] ⁺ ; t _R =0.96 min (LCMS method a).

Step B. 1-(4-Chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(4-Chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A ) (119 mg, 0.40 mmol) and NaOtBu (67 mg, 0.70 mmol) were stirred in toluene (3 mL) for 15 min. 2-Bromo-4-(2,2,2-trifluoroethoxy)pyridine (138 mg, 0.540 mmol) and bis(tri-tert-butylphosphine)palladium(0) (10 mg, 0.020 mmol) were added to the white suspension and the mixture was heated for 1 h at 90 °C. After cooling to rt, the reaction mixture was filtered through celite and the filtrate was concentrated. SFC purification (Reprosphere PEI 100Å, 5 μm, 30 × 250 mm; 6-16% MeOH in CO ₂ for 10 min) gave the title compound (97 mg, 0.20 mmol) as a white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.91 (d, 1H), 7.59 (dd, 1H), 7.24 (dd, 1H), 6.98 (dd, 1H), 6.33 (m, 2H), 4.77 (q, 2H), 4.07-4.18 (m, 2H), 2.89 (m, 2H), 2.44 (t, 2H), 2.12 (m, 2H), 1.84-1.88 (m, 4H) 1.51-1.59 (m, 2H) ppm; m/z=472.4 [M+H] ⁺ ; t _R =0.98 minutes (LCMS method a).

Example 82

Step A. 4-Chloro-6-(2,2,2-trifluoroethoxy)pyrimidine

NaH (60% in mineral oil, 831 mg, 20.8 mmol) was added portionwise to a stirred solution of 4,6-dichloropyrimidine (1.769 g, 11.88 mmol) and 2,2,2-trifluoroethanol (1.0 g, 9.9 mmol) in THF (100 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with saturated NH ₄ Cl solution, diluted with EtOAc and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (0-7% EtOAc in cyclohexane) gave 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine (1.51 g, 6.75 mmol). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.77 (s, 1H), 7.44 (s, 1H), 5.12 (q, 2H) ppm; m/z = 213.0 [M+H] ⁺ ; t _R = 0.96 minutes (LCMS method a).

Step B. 1-(3,4-Difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate connectionA, 750 mg, 2.68 mmol), 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine (1.137 g, 3.75 mmol) and triethylamine (1.12 mL, 8.03 mmol) were dissolved in EtOH (10 mL) and heated under microwave irradiation for 30 min at 160 °C. After cooling to rt, the reaction mixture was concentrated. Purification by silica gel chromatography (0-10% MeOH in DCM) afforded the title compound (667 mg, 2.26 mmol).¹H NMR (400 MHz, DMSO-d₆) δ=8.20 (s, 1H), 7.41 (m, 1H), 7.23 (m, 1H), 6.87-6.94 (m, 1H), 6.18 (s, 1H), 4.93 (q, 2H), 4.11-4.34 (m, 2H), 2.99 (br t, 2H), 2.42 (t, 2H), 2.12 (m, 2H), 1.80-1.90 (m, 4H) 1.42-1.56 (m, 2H) ppm; mass/charge=457.2 [M+H]⁺;t_R=1.07 minutes (LCMS method a).

Using methods similar to those described for the preparation of Example 82 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 83
1-(4-Chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 473.3; 1.14 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.21 (s, 1H), 7.59 (dd, 1H), 7.24 (dd, 1H), 6.95 (d, 1H), 6.19 (s, 1H), 4.94 (q, 2H), 4.14-4.32 (m, 2H), 2.99 (br t, 2H), 2.43 (t, 2H), 2.14 (m, 2H), 1.86 (m, 4H) 1.50 (m, 2H). ppm 84
1-(4-Chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 455.2; 1.05 min., LCMS method a ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.19 (s, 1H), 7.58 (t, 1H), 7.23 (dd, 1H), 6.95 (d, 1H), 6.31 (m, 1H), 6.12 (s, 1H), 4.51 (dt, 2H), 4.48 (m, 2H), 2.98 (br t, 2H), 2.43 (t, 2H), 2.13 (m, 2H), 1.86 (m, 4H) 1.53-1.50 (m, 2H). ppm 85
1-(3,4-Difluorophenyl)-9-(4-propoxypyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one 417.3; 0.68 min., LCMS method i ¹ H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=5.8 Hz, 1H), 7.42 (dt, J=10.8, 9.0 Hz, 1H), 7.23 (ddd, J=11.4, 7.5, 2.5 Hz, 1H), 6.92 (ddd, J=8.3, 4.2, 2.1 Hz, 1H), 5.98 (d, J=5.8 Hz, 1H), 4.58-4.41 (m, 2H), 4.15 (t, J=6.6 Hz, 2H), 2.97 (td, J=13.3, 2.5 Hz, 2H), 2.43 (t, J=6.8 Hz, 2H), 2.14 (s, 2H), 1.95-1.77 (m, 4H), 1.66 (h, J=7.1 Hz, 2H), 1.49 (td, J=13.5, 4.9 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). 86
rac -1-(3,4-Difluorophenyl)-9-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 471.2; 0.68 min., LCMS method i ^1H NMR (400 MHz, chloroform-d) δ 8.22 (s, 1H), 7.17 (m, 1H), 6.89 (m, 1H), 6.76-6.78 (m, 1H), 5.81 (s, 1H), 5.73 (m, 1H), 4.22 (t, 2H), 3.05-2.89 (m, 2H), 2.61 (t, 2H), 2.13-2.15 (m, 2H), 1.93-1.98 (m, 2H), 1.85-1.71 (m, 4H), 1.44 (d, 3H). 87
1-(3,4-Difluorophenyl)-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 459.4; 1.94 min., LCMS method k ^1H NMR (400 MHz, methanol- _d4 ) δ 8.11 (s, 1H), 7.44-7.36 (m, 1H), 7.28-7.2 (m, 1H), 6.92 (m, 1H), 5.98 (s, 1H), 5.28-5.15 (m, 1H), 4.24-4.1 (m, 2H), 3.83-3.79 (m, 2H), 3.43 (t, 2H), 2.93 (t, 2H), 2.41 (t, 2H), 2.12 (br, 2H), 1.98-1.8 (m, 6H), 1.6-1.41 (m, 4H). 88
9-(2-Chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 491.08; 0.71 min., LCMS method i 1H NMR (DMSO- _d6 , 300 MHz) δ 7.46-7.40 (m, 1H), 7.28-7.2 (m, 1H), 6.93-6.91 (m, 1H), 6.29 (s, 1H), 4.98 (q, 2H), 4.4 (br, 2H), 3.04 (t, 2H), 2.43 (t, 2H), 2.13 (br, 2H), 1.9-1.83 (m, 4H), 1.48 (br, 2H).

Example 89a (S)-9-(2-Amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

And

Example 89b. (R)-9-(2-Amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 2,2,2-Trifluoro-1-(oxetan-3-yl)ethan-1-ol

A solution of oxetane-3-carbaldehyde (1.80 g, 20.9 mmol) in THF (8 mL) was cooled to -70 °C and treated with trimethyl(trifluoromethyl)silane (5.94 g, 41.8 mmol) followed by treatment with tetrabutylammonium fluoride (5.46 g, 20.9 mmol). The reaction mixture was warmed to rt and stirred for 3 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give 2,2,2-trifluoro- _1- (oxetan-3-yl)ethan-1-ol (2.8 g, crude).

Step B. 4-Chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine

A stirred solution of 4,6-dichloropyrimidin-2-amine (2.20 g, 13.4 mmol) and 2,2,2-trifluoro-1-(oxetan-3-yl)ethan-1-ol (2.72 g, 17.4 mmol) in 1,4-dioxane (10 _mL ) was treated with _Cs2CO3 (13.11 g, 40.24 mmol). The reaction mixture was heated to 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (1% MeOH in DCM) gave 4-chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine (2.10 g, 55.2%). m/z = 284.0, [MH] ⁺ ; t _R = 1.45 min. (LCMS method l)

Step C. 9-(2-Amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of 4-chloro-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-2-amine (0.303 g, 1.07 mmol) and 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.300 g, 1.07 mmol) was treated with Cs₂CO₃(1.04 g, 3.21 mmol). The reaction mixture was heated to 80 °C for 15 h. The mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (GEMINI, 5 μm, 21.2 × 150 mm; elution with water/ACN) gave pure racemic material.¹H NMR (300 MHz, DMSO-d₆) δ 7.40 (m, 1H), 7.21 (m, 1H), 6.94-6.82 (m, 1H), 6.22 (s, 2H), 6.12 (m, 1H), 5.44 (s, 1H), 4.69-4.47 (m, 3H), 4.35 (t, 1H), 4.13 (brs, 2H), 3.57 (m, 1H), 2.87 (t, 2H), 2.39 (t, 2H), 2.08 (s, 2H), 1.72-1.82 (m, 4H), 1.55-1.34 (m, 2H). mass/charge=528.1, [M+H]⁺, t_R=1.53 minutes (LCMS method l). Chiral SFC (CHIRALPAK IA, 10 μm, 10 × 250 mm; mobile phase A: CO₂, mobile phase B: IPA; flow rate 15 ml/min.; isocratic elution A:B 77:23) were obtainedexample 89a(peak 1, 27 mg; SFC t_R=10.23 min.) andexample 89b(peak 2, 28 mg; SFC t_R=10.94 min.).

Using methods similar to those described for the preparation of Examples 89a and 89b using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 90
9-(2-Amino-6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 480.3; 0.55 min, LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.03 (s, 2H), 5.28 (s, 1H), 5.03-4.88 (m, 1H), 4.11 (brs, 2H), 2.97-3.06 (m, 2H), 2.84 (t, 2H), 2.55-2.63 (m, 2H), 2.41 (t, 2H), 2.08 (d, 2H), 1.78-1.85 (m, 4H), 1.43 (t, 2H). 91
9-(2-Amino-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 472.2; 0.61 min., LCMS method i ¹ H NMR (400 MHz, chloroform-d) δ 7.21 (dtd, J=10.0, 8.6, 3.4 Hz, 1H), 6.90 (ddd, J=10.6, 7.1, 2.5 Hz, 1H), 6.80 (dddd, J=8.4, 4.0, 2.5, 1.7 Hz, 1H), 5.37 (s, 1H), 4.68 (dq, J=12.9, 8.5 Hz, 2H), 4.16 (dd, J=28.3, 13.7 Hz, 2H), 3.01 (d, J=14.5 Hz, 2H), 2.62 (td, J=6.8, 3.6 Hz, 2H), 2.19-2.10 (m, 2H), 2.01-1.86 (m, 3H), 1.83 (s, 3H). 92
9-(2-Amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 474.2; 0.59 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.18 (s, 2H), 5.40 (s, 1H), 4.1-4.18 (m, 2H), 2.87 (t, 2H), 2.41 (t, 2H), 2.08-2.12 (m, 2H), 1.82 (m, 4H), 1.38-1.5 (m, 2H). 93
9-(2-Amino-6-isopropoxypyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 432.3; 0.49 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 5.92 (s, 2H), 5.18 (s, 1H), 5.12 (h, 1H), 4.18-3.97 (m, 2H), 2.82 (t, 2H), 2.41 (t, 2H), 2.15-2.02 (m, 2H), 1.91-1.75 (m, 4H), 1.4-1.45 (m, 2H), 1.16 (d, 6H). 94
9-(2-Amino-6-(2-hydroxyethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 434.1; 0.42 min., LCMS method i ^1H NMR (DMSO- _d6 , 300 MHz) δ 7.42-7.36 (m, 1H), 7.24-7.18 (m, 1H), 6.91-6.88 (m, 1H), 6.17 (br, 2H), 5.3 (s, 1H), 4.7 (br, 1H), 4.18-4.08 (m, 4H), 3.57 (t, 2H), 2.86 (t, 2H), 2.41-2.37 (m, 2H), 2.07 (br, 2H), 1.81-1.77 (m, 4H), 1.46-1.38 (m, 2H). 95
rac -9-(2-Amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 486.2; 0.68 min., LCMS method i ^1H NMR (600 MHz, chloroform-d) δ 7.16 (m, 1H), 6.87 (m, 1H), 6.76 (d, 1H), 4.80 (s, 2H), 4.69-4.56 (m, 4H), 3.06 (t, 2H), 2.86 (t, 2H), 2.60 (t, 2H), 2.13 (brs, 2H), 1.88-1.98 (m, 4H), 1.80-1.72 (m, 6H). 96
rac -9-(2-Amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 542.3; 2.05 min., LCMS method k ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.41 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.25 (s, 2H), 6.14 (m, 1H), 5.44 (s, 1H), 4.61 (d, 1H), 4.47 (d, 1H), 4.21 (d, 2H), 4.13 (d, 2H), 2.88 (t, 2H), 2.41 (t, 2H), 2.15-2.04 (m, 2H), 1.89-1.76 (m, 3H), 1.46 (s, 4H). 97
9-(2-Amino-6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 522.2; 0.64 min., LCMS method i ^1H NMR (300 MHz, DMSO-d ₆ ) δ?7.41 (m, 1H), 7.22 (m, 1H), 6.91 (m, 1H), 6.20 (s, 2H), 5.38 (s, 1H), 4.92 (t, 2H), 4.25-4.00 (m, 2H), 2.88 (t, 2H), 2.41 (t, 2H), 2.18-2.04 (brs, 2H), 1.72-1.9 (m, 4H), 1.36-1.5 (m, 2H). 98
rac -9-(2-Amino-6-((4,4-difluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 496.3; 1.16 min., LCMS method k ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.45 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.11 (s, 2H), 5.49 (dt, 1H), 5.36 (s, 1H), 4.29 (m, 1H), 4.22-3.69 (m, 4H), 2.87 (t, 2H), 2.47-2.33 (m, 2H), 2.09 (d, 2H), 1.72-1.88 (m, 4H), 1.38-1.5 (m, 2H). 99
rac -9-(2-Amino-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 492.3; 0.51 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (d, 1H), 6.05 (s, 2H), 5.29 (s, 1H), 5.19-5.22 (m, 1H), 4.58 (d, 1H), 4.11 (brs, 2H), 3.82-3.94 (m, 2H), 3.77-3.64 (m, 1H), 3.55-3.42 (m, 2H), 2.85 (t, 2H), 2.41 (t, 2H), 2.15-2.01 (m, 3H), 1.77-1.88 (m, 3H) 100
(R)-9-(2-Amino-6-((tetrahydro-2H-pyran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 474.3; 0.79 min., LCMS method k ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.39 (m, 1H), 7.20 (m, 1H), 6.94-6.81 (m, 1H), 5.96 (s, 2H), 5.21 (s, 1H), 4.8-4.9 (m, 1H), 3.74 (dd, 2H), 3.51-3.62 (m, 1H), 3.35-3.46 (m, 1H), 3.26-3.32 (m, 1H), 2.81 (t, 2H), 2.39 (t, 3H), 1.67-1.88 (m, 8H), 1.32-1.5 (m, 4H). 101
9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 474.4; 0.17 min., LCMS method l ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.37 (m, 1H), 7.21 (m, 1H), 6.90 (m, 1H), 5.22 (s, 1H), 4.98-5.03 (m, 1H), 4.09 (d, 2H), 3.75-3.82 (m, 2H), 3.42-3.34 (m, 4H), 2.82 (t, 2H), 2.40 (t, 2H), 2.15-1.99 (m, 2H), 1.93-1.71 (m, 5H), 1.41-1.52 (m, 3H). 102
rac -9-(2-Amino-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one 478.3; 0.52 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 6.11 (s, 2H), 5.41 (dd, 2H), 5.28 (m, 1H), 5.14 (d, 1H), 4.02-4.14 (m, 2H), 3.86-3.94 (m, 2H), 3.68-3.72 (m, 1H), 3.62-3.68 (m, 1H), 2.85 (t, 2H), 2.41 (t, 2H), 2.09 (s, 2H), 1.77-1.81 (m, 4H), 1.48-1.52 (d, 2H).

Example 103. 9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. tert-Butyl-(tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate

Stirred solution 4,6-Dichloropyrimidin-2-amine (10.00 g, 60.97 mmol) in THF (100 mL) was treated with DMAP (0.744 g, 6.10 mmol) and di-tert-butyl dicarbonate (29.27 g, 134.1 mmol) and stirred at rt for 12 h. The reaction mixture was quenched by adding ice and then extracted with EtOAc. The combined extracts were washed with aqueous NaHCO₃, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded tert-butyl (tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate (16.23 g) as a light brown liquid.¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (s, 1H), 1.4 (s, 18 H).

Step B. tert-Butyl (tert-butoxycarbonyl) (4-chloro-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate

A stirred solution of tert-butyl (tert-butoxycarbonyl)(4,6-dichloropyrimidin-2-yl)carbamate (0.500 g, 1.37 mmol) in dioxane (7 mL) was treated with tetrahydro-2H-pyran-4-d-4-ol (0.170 g, 1.65 mmol) and Cs₂CO₃(1.342 g, 4.118 mmol). The reaction mixture was stirred at 80°C for 12 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material (0.56 g) was used as is in the next step without any purification. Mass/charge=431.1, [M+H]⁺;t_R=1.68 min. (LCMS method j).

Step C. tert-Butyl (tert-butoxycarbonyl)(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A, 0.300 g, 1.07 mmol) and DIPEA (0.56 mL, 3.2 mmol) were added to a stirred solution of tert-butyl (tert-butoxycarbonyl)(4-chloro-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate (0.553 g, 1.28 mmol) in EtOH (7 mL). The reaction mixture was heated to 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure. The crude material (0.788 g) was used as _is in the next step without purification. m/z=675.2, [M+H] ⁺ ; t _R =1.60 min (LCMS method j).

Step D. 9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A solution of hydrochloric acid (4.0 M in dioxane, 15 mL) was added to a stirred solution of tert-butyl (tert-butoxycarbonyl)(4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-2-yl)carbamate (0.780 g, 1.16 mmol) in dioxane (5 mL). The reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in saturated aqueous NaHCO₃The mixture was extracted with EtOAc. The combined extracts washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (LUNA Phenomenex, 5.0 μm, 21.2 × 250 mm; eluting with 0.01% HCOOH in water:ACN) afforded the title compound as an off-white solid (78 mg).¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (brs, 2H), 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (m, 1H), 5.23 (s, 1H), 4.11 (d, 2H), 3.80 (dt, 2H), 3.40 (t, 2H), 2.83 (t, 2H), 2.41 (t, 2H), 2.02-2.12 (m, 2H), 1.71-1.9 (m, 6H), 1.35-1.52 (m, 4H); mass/charge=475.2 [M+H]⁺;t_R=1.31 minutes (LCMS method j).

Example 104. rac-9-(2-Amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step-A. 4-Fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine

Sodium hydride (0.183 g, 7.63 mmol) was added portionwise to a stirred solution of 3-methyltetrahydrofuran-3-ol (0.311 g, 3.05 mmol) in THF (5 mL) at 0 °C and stirred at the same temperature for 30 min. A solution of 4,6-difluoropyrimidin-2-amine (0.200 g, 1.52 mmol) in THF (5 mL) was added and the mixture was stirred at rt for 16 h. Saturated aqueous NH ₄ Cl solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Preparative TLC purification (30% EtOAc in hexanes) afforded 4-fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (0.163 g) as an off-white solid. m/z = 214.2 [M+H] ⁺ ; t _R = 0.41 min (LCMS method l).

Step B. 9-(2-Amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

1-(3,4-Difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.214 mg, 0.764 mmol) and DIPEA (0.40 mL, 2.3 mmol) were added to a stirred solution of 4-fluoro-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (0.163 mg, 0.764 mmol) in EtOH (1 mL) at rt. The reaction mixture was heated at 80 °C for 48 h. The mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (10% MeOH in DCM) to give the title compound (0.125 mg) as an off-white solid. ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.23 (m, 1H), 6.91 (ddd, 1H), 5.93 (s, 2H), 5.19 (s, 1H), 4.09 (d, 2H), 3.92 (d, 1H), 3.70-3.78 (m, 3H), 2.82 (t, 2H), 2.48-2.27 (m, 4H), 2.05-2.15 (m, 2H), 1.72-1.9 (m, 4H), 1.59 (s, 3H), 1.32-1.5 (m, 2H); mass/charge=474.3 [M+H] ⁺ ; t _R = 0.50 minutes (LCMS method i).

Example 105. rac -9-(2-Amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. 6-Chloro-2-(methylthio)pyrimidin-4-ol

A stirred solution of 4,6-dichloro-2-(methylthio)pyrimidine (5.0 g, 25.6 mmol) in 2 M NaOH (125 mL) was heated at 120 °C for 5 h. The reaction mixture was cooled to rt and acidified to pH 6 by slow addition of AcOH. The resulting white solid was isolated by filtration and dried under vacuum to give 6-chloro-2-(methylthio)pyrimidin-4-ol as an off-white solid (4.07 g, crude). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.1 (brs, 1H), 6.22 (s, 1H), 2.5 (s, 3H).

Step B. 4-Chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidine

A stirred solution of 6-chloro-2-(methylthio)pyrimidin-4-ol (3.40 g, 32.0 mmol) and triphenylphosphine (11.6 g, 44.2 mmol) in THF (100 mL) was treated with (3R,4R)-4-fluorotetrahydrofuran-3-ol (2.00 g, 11.3 mmol) and DIAD (7.67 g, 37.9 mmol). The reaction mixture was heated to 80 °C for 12 h. After cooling to rt, the mixture was diluted with pentane and the solvent was decanted. The decanted solvent was concentrated under reduced pressure. Purification by silica gel chromatography (10% EtOAc in hexane) afforded 4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidine

as an off-white solid (1.82 g). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.96 (s, 1H), 5.59-5.32 (m, 2H), 4.11-4.01 (m, 2H), 3.97-3.78 (m, 2H), 2.53 (s, 3H).

Step C. 4-Chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidine

A stirred solution of 4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylthio)pyrimidine (1.80 g, 6.80 mmol) in THF (30 mL) and water (7 mL) was treated with Oxone® (6.20 g, 20.4 mmol). The reaction mixture was stirred at rt for 3 h, then diluted with water and extracted twice with EtOAc. The organic extracts were washed with NaHCO solution₃, saline solution, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude material (1.86 g) was used as is in the next step without any purification.¹H NMR (400 MHz, DMSO-d₆) δ 7.68 (s, 1H), 5.65-5.41 (m, 2H), 4.14-3.87 (m, 4H), 3.45 (s, 3H).

Step D. 1-(3,4-Difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 4-chloro-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidine (1.00 g, 3.57 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 1.06 g, 3.57 mmol) and DIPEA (1.38 g, 10.7 mmol) in EtOH (8 mL) was heated at 80 °C for 1 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined extracts were washed with NaHCO3 solution, brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give _1- (3,4-difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (0.643 g). m/z = 541.1 [M+H] ⁺ ; t _R = 0.93 min (LCMS method l).

Step E. 9-(2-Azido-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (0.640 g, 1.18 mmol) and sodium azide (0.900 g, 13.8 mmol) in DMF (15 mL) was heated at 50 °C for 24 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The extracts were washed with aqueous NaHCO ₃ solution, brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material (0.651 g) was used as is in the next step without further purification. Mass/charge = 504.4 [M+H] ⁺ ; t _R = 2.18 min. (LCMS method l).

Step F. 9-(2-Amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of 9-(2-azido-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (0.651 g, 1.29 mmol) in THF (6 mL) was cooled to -78^oC. Trimethylphosphine (0.108 g, 1.42 mmol) was added and the temperature was gradually raised to rt. The mixture was stirred at rt for 12 h, then heated at 50 °C for 24 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The extracts were washed with NaHCO solution.₃, saline solution, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (Acquity XSelect, 5.0 μm, 21.2 × 250 mm; mobile phase 0.02% NH₄OH in a water:ACN mixture) gave the title compound (0.356 g) as an off-white solid.¹H NMR (300 MHz, chloroform-d) δ 7.17 (m, 1H), 6.88 (m, 1H), 6.77 (m, 1H), 5.34 (m, 2H), 5.17 (m, 1H), 4.56 (s, 2H), 4.22-4.07 (m, 3H), 4.06-3.94 (m, 1H), 3.87-3.76 (m, 2H), 2.8-2.95 (m, 2H), 2.60 (t, 2H), 2.18-2.05 (m, 2H), 1.88-1.95 (m, 2H), 1.7-1.78 (m, 4H); mass/charge=478.2 [M+H]⁺, t_R=0.50 minutes (LCMS method i).

Example 106. 1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Step A. Methyl 4-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate

A mixture of _methyl 4,6-dichloropyrimidine-2-carboxylate (300 mg, 1.45 mmol), tetrahydro-2H-pyran-4-ol (148 mg, 1.45 mmol) and _Cs2CO3 (944 mg, 2.90 mmol) in dioxane (5 mL) was heated to 80 °C for 2 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give methyl 4-chloro- ₆ -((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (130 mg), which was used without purification.

Step B. Methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate

A mixture of methyl 4-chloro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (130 mg, 0.476 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 133 mg, 0.476 mmol) and DIPEA (0.18 mL, 1.4 mmol) in EtOH was heated at 80 °C for 2 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts _were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (120 mg, crude). m/z = 517.2 [M+H] ⁺ ; t _R = 1.31 min (LCMS method k).

Step C. 1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

A stirred solution of methyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidine-2-carboxylate (120 mg, 0.232 mmol) in MeOH (5 mL) was treated with sodium borohydride (35 mg, 0.93 mmol) at 0°C. The mixture was stirred at rt for 2 h. The mixture was diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Purification by preparative HPLC (LUNA C18, 5 μm, 21.2 × 250 mm; elution with 0.1% HCOOH:MeCN) gave the title compound (5 mg).¹H NMR (400 MHz, DMSO-d₆) δ 7.42 (m, 1H), 7.24 (m, 1H), 6.90-6.92 (m, 1H), 5.84 (s, 1H), 5.11-5.2 (m, 1H), 4.70 (t, 1H), 4.23 (d, 3H), 3.78-3.83 (m, 2H), 3.45 (t, 2H), 2.92 (t, 2H), 2.42 (t, 2H), 2.11 (brs, 2H), 1.83-1.92 (m, 5H), 1.57-1.57 (m, 4H); mass/charge=489.3 [M+H]⁺;t_R=1.1 minutes (LCMS method k).

Using methods similar to those described for the preparation of Example 106 using suitable starting materials, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 107
rac -1-(3,4-Difluorophenyl)-9-(6-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 507.3; 0.57 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.25 (m, 1H), 6.92 (d, 1H), 5.92 (s, 1H), 5.25-5.32 (m, 1H), 4.82 (d, 1H), 4.74 (t, 1H), 4.24 (d, 3H), 3.84-3.98 (m, 2H), 3.46-3.65 (m, 2H), 2.94 (t, 2H), 2.42 (t, 2H), 2.11 (brs, 2H), 1.83-1.91 (m, 4H), 1.41-1.52 (m, 2H). 108
rac -1-(3,4-Difluorophenyl)-9-(6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 493.2; 0.58 min., LCMS method i ^1H NMR (400 MHz, DMSO- _d6 ) δ?7.42 (m, 1H), 7.24 (m, 1H), 6.92 (d, 1H), 5.92 (s, 1H), 5.52 (d, 1H), 5.25 (d, 1H), 4.78 (t, 1H),
4.26 (d, 2H), 4.13 (dd, 1H), 4.02-3.78 (m, 2H), 3.68 (d, 1H), 2.94 (t, 2H), 2.42 (t, 2H), 2.12 (brs, 2H), 1.80-1.88 (m, 3H), 1.46 (t, 2H). 109
(S)-1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 475.2; 0.55 min, LCMS method i ^1H NMR (300 MHz, methanol- _d4 ) δ?7.27 (m, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 5.78 (s, 1H), 5.52 (m, 1H), 4.38 (s, 2H), 4.3 (m, 2H), 3.82-3.95 (m, 4H), 3.02 (t, 2H), 2.56 (t, 2H), 2.18-2.25 (m, 3H), 1.88-2.01 (m, 5H), 1.7 (brs, 2H).

Example 110a (S)-1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or (R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

And

Example 110b. (R)-1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

Racemic 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one or (R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one was synthesized in a similar manner to that used for Example 106 using rac -1,1,1-trifluoropropan-2-ol. ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.24 (m, 1H), 6.98-6.84 (m, 1H), 6.00 (s, 1H), 5.94 (m, 1H), 4.84 (t, 1H), 4.26 (d, 3H), 2.96 (t, 2H), 2.42 (t, 2H), 2.18-2.04 (m, 2H), 1.91-1.78 (m, 4H), 1.47 (t, 2H), 1.37 (d, 3H); mass/charge=501.1 [M+H] ⁺ ; t _R =1.63 (LCMS method l). The racemic product was purified by chiral HPLC (Phenomenex Lux Cellulose, 4 μm, 21.2 x 250 mm; mobile phase A: hexane, mobile phase B: EtOH; isocratic elution 70(A):30(B); flow rate 15 mL/min) to give example 110b (peak 1; chiral HPLC t _R = 3.57 min) and example 110a (peak 2; chiral HPLC t _R = 3.94 min).

Example 111. rac -Ethyl-4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-2-carboxylate

Stage A. rac -(3R,4R)-4-Fluorotetrahydrofuran-3-ol.

Triethylamine trihydrofluoride (60 mL) was added to 3,6-dioxabicyclo[3.1.0]hexane (10.00 g, 116.1 mmol) at rt. The mixture was then heated at 120 °C for 12 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The extracts were washed with brine and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (100% EtOAc) gave rac- (3R,4R)-4-fluorotetrahydrofuran-3-ol (8.0 g) as a brown liquid. ^1H NMR (300 MHz, DMSO- _d6 ) δ 5.42 (d, 1H), 5.21-5.25 (m, 1H), 3.77-3.9 (m, 2H), 3.53-3.56 (m, 1H), 3.34 (br s, 1H).

Stage B. rac -Methyl 4-chloro-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate.

A mixture of methyl 4,6-dichloropyrimidine-2-carboxylate (0.150 g, 0.724 mmol),rac-(3R,4R)-4-fluorotetrahydrofuran-3-ol (0.076 g, 0.72 mmol) and Cs₂CO₃(0.472 g, 1.45 mmol) in dioxane (5 mL) was stirred at rt for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to giverac-methyl 4-chloro-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate (0.160 g) as a yellow gummy solid, which was used without further purification. Mass/charge = 277.1 [M+H]⁺;t_R=0.47 min. (LCMS method l).

Stage C. rac -Ethyl 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-2-carboxylate.

A mixture of 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound A, 0.045 g, 0.16 mmol),rac-methyl-4-chloro-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-2-carboxylate (0.060 g, 0.22 mmol) and DIPEA (110 µL, 0.65 mmol) in EtOH (2 mL) were heated at 80 °C for 2 h. The mixture was cooled to rt, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. Purification was performed by preparative HPLC (LUNA Phenomenex, 5 μm, 21.2 × 250 mm; elution with 0.1% HCOOH in H₂O:ACN) gave the title compound (3 mg) as an off-white solid.¹H NMR (400 MHz, methanol-d₄) δ 7.24 (m, 1H), 7.09 (m, 1H), 6.91 (m, 1H), 6.07 (s, 1H), 5.54-5.58 (m, 1H), 5.2 (d, 1H), 4.22-4.34 (m, 4H), 4.17-4.22 (m, 1H), 4.03 (s, 1H), 3.92-3.94 (m, 1H), 3.8 (d, 1H), 3.07 (t, 2H), 2.57 (t, 2H), 2.18-2.3 (m, 2H), 1.91-2.01 (m, 4H), 1.7 (brs, 2H), 1.29 (m, 3H); mass/charge=535.3 [M+H]⁺;t_R=2.13 minutes (LCMS method l).

Example 112. (R)-9-(2-Amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one.

Step A. ( R )-6-Chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine

Mixture 4,6-Dichloropyrimidin-2-amine (0.300 g, 1.83 mmol), (R)-tetrahydrofuran-3-amine (0.120 g, 1.37 mmol), and DIPEA (0.96 mL, 5.5 mmol) in EtOH (5 mL) were heated at 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was triturated with pentane to give (R)-6-chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.25 g, 64%) as an off-white solid. W/C=215.0 [M+H]⁺;t_R=0.64 min. (LCMS method l).

Step B. ( R )-6-Fluoro-N4-(tetrahydrofuran-3-yl)pyrimidin-2,4-diamine

A mixture of ( R )-6-chloro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.100 g, 0.465 mmol) and CsF (0.283 g, 1.86 mmol) in DMSO (5 mL) was heated at 150 °C for 24 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. Triturating the crude product with pentane gave ( R )-6-fluoro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.15 g, crude). Mass/charge=199.2 [M+H] ⁺ ; t _R =0.43 min. (LCMS method k).

Step C. ( R )-9-(2-Amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of ( R )-6-fluoro-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (0.100 g, 0.502 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 0.106 g, 0.376 mmol) and DIPEA (0.26 mL, 1.5 mmol) in EtOH (3 mL) was heated to 80 °C for 72 h. The reaction mixture was cooled to rt, diluted with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by preparative HPLC (Waters XSelect, 5 μm, 21.2 x 250 mm; mobile phase 0.02% NH ₄ OH in H ₂ O:ACN) gave the title compound as an off-white solid (20 mg). ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.43 (m, 1H), 7.24 (m, 1H), 6.92 (s, 1H), 6.34 (d, 1H), 5.46 (s, 2H), 4.94 (s, 1H), 4.26 (s, 1H), 4.01 (d, 1H), 3.6-3.82 (m, 2H), 2.87-2.56 (m, 3H), 2.32-2.54 (m, 2H), 2.16-1.92 (m, 3H), 1.6-1.76 (m, 4H), 1.44 (s, 3H), 1.32-1.5 (m, 2H); mass/charge=459.2 [M+H] ⁺ ; t _R =1.30 minutes (LCMS method j).

Example 113a. (R)-9-(2-Amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

And

example 113b. (S)-9-(2-Amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one or (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

Stage A. rac -4-Chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine

To a solution of 4,6-dichloropyrimidin-2-amine (5.00 g, 30.5 mmol) in 1,4-dioxane (125 mL) were added 1,1,1-trifluoropropan-2-ol (5.20 g, 45.7 mmol) and _Cs2CO3 (29.80 g, 91.46 mmol). The mixture was stirred at 80 °C for 16 _h . The reaction mixture was cooled to rt, diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure to give 4-chloro- ₆ -((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine (7.40 g) as a yellow solid. Mass/charge = 242.1 [M+H] ⁺ ; t _R = 0.76 min. (LCMS method l).

Stage B. rac -9-(2-Amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one

Into suspensionrac-4-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-2-amine (7.40 g, 29.4 mmol) in EtOH (200 mL) was added 1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one (intermediate compound E, 9.40 g, 29.4 mmol). DIEA (26.60 g, 205.7 mmol) was added dropwise at 25 °C. The mixture was stirred at 80 °C for 24 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. Purification by silica gel chromatography (100% EtOAc) gave racemic 9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one (4.4 g) as a yellow solid.¹H NMR (300 MHz, DMSO-d₆) δ 7.49-7.29 (m, 2H), 7.00-7.03 (m, 1H), 6.17 (s, 2H), 5.65-5.78 (m, 1H), 5.37 (s, 1H), 4.35 (t, 2H), 4.15 (brs, 2H), 2.83 (t, 2H), 2.30 (t, 2H), 1.84 (d, 2H), 1.47-1.35 (m, 2H), 1.32 (d, 3H); mass/charge=488.2 [M+H]⁺;t_R=0.64 minutes (LCMS method i). By means of chiral SFC (Waters UPCC; Chiralpak IG-3, 3 μm, 4.6 × 250 mm, 35°C; mobile phase A: CO₂, mobile phase B: 0.1% DEA in MeOH, isocratic elution: 40% B for 7 min; flow rate 2.5 ml/min; UV detection, 210 nm) were obtainedexample 113a(peak 1, 0.974 g; SFC t_R=4.41 min.) andexample 113b(peak 2, 1.20 g; SFC t_R=5.10 min.).

Example 114 was synthesized using methods similar to those described for the preparation of Examples 65 and 66 using intermediate E. Example 115 was synthesized using methods similar to those described for the preparation of Example 64 using intermediate E.

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 114
1-(3,4-Difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one 525.2; 0.64 min., LCMS method i ^1H NMR (300 MHz, DMSO- _d6 ) δ 9.30 (s, 1H), 8.30 (s, 1H), 7.51-7.32 (m, 2H), 7.03-7.07 (m, 1H), 6.98 (s, 1H), 4.98 (brs, 1H), 4.49-4.24 (m, 5H), 3.08 (t, 2H), 2.38 (t, 3H), 1.98 (d, 2H), 1.42-1.6 (m, 2H). 115
9-(2-Amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one 510.2; 0.65 min, LCMS method i ¹ H NMR (300 MHz, chloroform-d) δ 8.72 (s, 1H), 7.84 (s, 1H), 7.13-7.22 (m, 1H), 6.86-7.01 (m, 2H), 6.52 (s, 1H), 4.77 (s, 2H), 4.52-4.31 (m, 4H), 2.94-3.0 (m, 2H), 2.35 (t, 2H), 1.74-1.82 (m, 4H).

Example 116a. ( R )-9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one or ( S )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

And

example 116b. ( S )-9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one or ( R )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

Step A. 4-Fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine

Sodium hydride (5.48 g, 137 mmol) was added portionwise to a solution of tetrahydro-2H-pyran-4-ol (11.7 g, 114 mmol) in THF (150 mL) cooled to 0 °C. 4,6-Difluoropyrimidin-2-amine (15 g, 114 mmol) was added and the mixture was stirred at rt for 12 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-20% EtOAc in petroleum ether) gave 4-fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine (10.5 g, 49 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.18-6.91 (m, 2H), 5.72-5.57 (m, 1H), 5.23-5.05 (m, 1H), 3.92-3.77 (m, 2H), 3.52-3.37 (m, 2H), 2.06-1.88 (m, 2H), 1.66-1.51 (m, 2H).

Step B. 9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one ( intermediate D , 9.3 g, 28 mmol), DIEA (1.2 mL, 70 mmol) and 4-fluoro-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-2-amine (6.0 g, 28 mmol) in EtOH (70 mL) was stirred at 80 °C for 12 h. After cooling to rt, the mixture was diluted with water and extracted with EA. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% MeOH in DCM) gave 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one (10 g, 20 mmol) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.50-7.37 (m, 1H), 7.30-7.17 (m, 1H), 6.97-6.84 (m, 1H), 6.08-5.90 (m, 2H), 5.78-5.74 (m, 2H), 5.29-5.22 (m, 1H), 5.09 (d, 1H), 5.07-5.00 (m, 1H), 4.27-3.97 (m, 3H), 3.85-3.75 (m, 2H), 3.43-3.36 (m, 2H), 2.94-2.79 (m, 2H), 2.76-2.66 (m, 1H), 2.59 (m, 1H), 2.38-2.21 (m, 1H), 1.92-1.82 (m, 3H), 1.80-1.63 (m, 2H), 1.54-1.47 (m, 2H), 1.39-1.20 (m, 1H); mass/charge=490.2

Step C. 9-(2-Amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one

DAST (3.96 g, 24.6 mmol) was added to a stirred solution of 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-hydroxy-1,9-diazaspiro[5.5]undecan-2-one (6.0 g, 12 mmol) in DCM (60 mL) at 0 °C. The mixture was allowed to warm to 25 °C and stirred for one hour. The reaction mixture was poured into water and extracted with DCM. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0-5% MeOH in DCM) gave racemic 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one (5.8 g, 11.8 mmol) as a yellow solid. ^1H NMR (400 MHz, chloroform-d) δ=7.25-7.14 (m, 1H), 7.00-6.87 (m, 1H), 6.86-6.72 (m, 1H), 5.32-5.08 (m, 3H), 4.69-4.44 (m, 2H), 4.32-4.10 (m, 2H), 3.99-3.89 (m, 2H), 3.61-3.49 (m, 2H), 3.09-2.86 (m, 4H), 2.66-2.47 (m, 1H), 2.45-2.21 (m, 1H), 2.07-1.95 (m, 3H), 1.81-1.65 (m, 5H); m/z=492.2 [M+H] ⁺ ; t _R =0.48 min (LCMS method i). Chiral SFC (Chiralpak AD-3, 3 μm, 4.6 x 50 mm, 35°C; mobile phase A: CO ₂ , mobile phase B: 0.05% DEA in EtOH; isocratic elution, 40% B over A; flow rate: 3 mL/min; detector: DAD) afforded example 116a (peak 1, 6.473 g; SFC t _R =1.54 min; m/z=492.2 [M+H] ⁺ ) and example 116b (peak 2, 5.998 g; SFC t _R =3.55 min; m/z=492.2 [M+H] ⁺ ).

Using methods similar to those described for the preparation of Example 116 using the appropriate starting materials described herein, the following compounds were prepared:

Note: Structure and name MS, mass/charge [M+H] ⁺ ;t _R , way ¹ H NMR 117
rac -9-(2-Amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one 510.2; 1.57 min., LCMS method l ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.42 (m, 1H), 7.24 (brs, 1H), 6.93 (brs, 1H), 6.53 (brs, 2H), 6.32 (s, 1H), 5.25 (d, 1H), 4.25 (brs, 2H), 2.9-3.11 (m, 3H), 2.48-2.78 (m, 4H), 1.88 (t, 2H), 1.32-1.52 (m, 2H). 118
rac -1-(3,4-Difluorophenyl)-4-fluoro-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one 477.2; 1.99 min., LCMS method k ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.15 (s, 1H), 7.44 (m, 1H), 7.35-7.16 (m, 1H), 6.95 (s, 1H), 6.00 (s, 1H), 5.42-5.12 (m, 2H), 4.21 (brs, 2H), 3.81 (dt, 2H), 3.55-3.34 (m, 2H), 3.14-2.88 (m, 3H), 2.58-2.7 (m, 2H), 1.8-1.95 (m, 4H), 1.38-1.6 (m, 4H).

Example 119

Step A. 1-(3,4-Difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

To 125 ml of thawed E. coli expressing cytochrome P450 3A4b5N1 (80<OD ₆₀₀ <100) were added 375 ml of PSE buffer, 25 ml of sodium citrate (50 g/100 ml) and 200 mg of 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one in 3 ml of DMSO. The mixture was stirred in a 3 l plastic Erlenmeyer flask equipped with 4 baffles and a breathable cap. 1-Octanol (50 μl) was added as an antifoam. The mixture was stirred in an Infors HT Multitron shaker at 30°C at 100 rpm. for 5 h. The mixture was extracted with 2 × 1 L EtOAc. The organic extracts were dried over MgSO ₄ , filtered and concentrated to dryness to give 600 mg of a blue solid. The crude material was dissolved in 4 mL DMSO and purified by preparative HPLC (column Vario-Prep HPLC VP 250/21 Nucleodur® 100-10 C18ec; mobile phase A: water + 0.1% HCOOH, mobile phase B: ACN + 0.1% HCOOH; flow rate: 40 mL/min; gradient elution 0-70% B over 25 min, 70% B over 5 min). 1-(3,4-Difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one was isolated with a UV purity of 82%. The isolated material was subjected to a second purification by preparative HPLC (gradient elution 20-60% B for 20 min, 60% B for 5 min) to give 1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (40.5 mg, 18.6% yield, UV purity >95%). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.21 (d, J=0.9 Hz, 1H), 7.50-7.37 (m, 1H), 7.24 (s, 1H), 6.92 (s, 1H), 6.20 (d, J=0.9 Hz, 1H), 5.10 (d, J=4.4 Hz, 1H), 4.93 (q, J=9.1 Hz, 2H), 4.24 (s, 2H), 4.13 (dt, J=13.9, 7.1 Hz, 1H), 3.00 (t, J=13.2 Hz, 2H), 2.72 (dd, J=17.1, 5.6 Hz, 1H), 2.61 (t, J=1.9 Hz, 1H), 2.36-2.28 (m, 1H), 1.93 (d, J=13.3 Hz, 1H), 1.85 (d, 1H), 1.75 (s, 1H), 1.57 (t, 1H), 1.36 (s, 1H); m/z=473.2 [M+H] ⁺ ; t _R =0.63 minutes (LCMS method i)

Step B. 1-(3,4-Difluorophenyl)-4-fluoro-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one

In a bottle of volume 10 mL of 1-(3,4-difluorophenyl)-4-hydroxy-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one (19 mg, 0.040 mmol) was dissolved in DCM (0.40 mL) and DAST (11 μL, 0.080 mmol) in DCM was added at 0 °C. After stirring for 10 min, the reaction mixture was allowed to warm to rt and stirred overnight. The mixture was quenched with saturated NaHCO₃, stirred for 20 min and extracted with EtOAc. The extracts were washed with brine, dried over MgSO₄, filtered and concentrated. Purification by reverse phase flash chromatography (RediSep® Rf Gold® reverse phase C18 column, 0-90% ACN in water). Fractions containing the product were combined, frozen and lyophilized to give the title compound (10 mg, 0.020 mmol).Note that any enantiomeric excess that may have been introduced during CYP450 oxidation in step A was not determined..¹H NMR (400 MHz, methylene chloride-d2) δ 7.12 (dd, J=8.5, 4.3 Hz, 1H), 6.93-6.82 (m, 1H), 6.82-6.69 (m, 1H), 5.81 (d, J=4.2 Hz, 1H), 5.20 (d, J=23.9 Hz, 1H), 4.66 (s, 2H), 4.19 (dd, J=27.7, 13.5 Hz, 2H), 3.12-2.66 (m, 4H), 2.44 (dt, J=15.4, 7.8 Hz, 1H), 2.39-2.25 (m, 1H), 1.99-1.86 (m, 1H), 1.69 (ddd, J=24.1, 10.9, 4.2 Hz, 3H), 1.53 (d, J=20.5 Hz, 1H); mass/charge=475.3 [M+H]⁺;t_R=0.65 minutes (LCMS method i).

Example 120

Step A. 2-Amino-6-(1,1-difluoroethyl)pyrimidin-4-ol

A mixture of ethyl 4,4-difluoro-3-oxopentanoate (3.00 g, 16.6 mmol), guanidine hydrochloride (3.2 g, 33 mmol), and sodium ethoxide (2.7 g, 50 mmol) in EtOH (40 mL) was heated at 80 °C for 5 h. The reaction mixture was concentrated under reduced pressure and diluted with water and EtOAc. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 2-amino-6-(1,1-difluoroethyl)pyrimidin-4-ol as an off-white solid (5.4 g). m/z = 176.1 [M+H] ⁺ ; t _R = 0.87 min (LCMS method j).

Step B. 9-(2-Amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one

A mixture of 2-amino-6-(1,1-difluoroethyl)pyrimidin-4-ol (1.50 g, 7.75 mmol), 1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one ( intermediate A , 1.08 g, 3.87 mmol), PyBrop (5.40 g, 11.6 mmol), and triethylamine (2.3 mL, 23 mmol) in dioxane (10 mL) was stirred at rt for 12 h. The reaction mixture was poured into ice water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc) gave the title compound (0.42 g). ¹ H NMR (300 MHz, methanol-d4) δ 7.41 (m, 1H), 7.29 (m, 1H), 7.09 (m, 1H), 6.28 (s, 2H), 6.12 (s, 1H), 4.31 (brs, 2H), 2.91 (t, 2H), 2.41 (t, 2H), 2.20 (br s, 2H), 1.71-1.9 (m, 7H), 1.4-1.52 (m, 2H); m/z = 438.2 [M+H] ⁺ ; t _R = 0.61 minutes (LCMS method l).

Claims (162)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ is one of where the asterisk * denotes the linkage position or R ¹ to N; R ² represents H or fluorine; X ¹ is CH ₂ ; R ⁴ is selected from the group consisting of pyrimidinyl, pyrazinyl, triazolyl, triazinyl, pyridinyl, pyridine oxide, quinazolinyl, pyrazolopyrimidinyl, benzooxazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, oxazolyl and thiazolyl, each of which is optionally substituted with one or more R ³ substituents; wherein each R ³ is independently selected from C ₆ aryl, benzyl, C ₁ alkyl, C ₁ alkoxy-C _1-3 alkyl, halogen, halo-C _1-2 alkyl, OR ⁵ , OH, C _3-6 cycloalkyl, C ₆ cycloalkenyl, 5-10-membered heteroaryl containing from 1 to 3 heteroatoms selected from nitrogen and oxygen, 4-7-membered heterocyclyl containing from 1 to 2 heteroatoms selected from nitrogen and oxygen, -C(O)NH ₂ and NR ^a R ^b , wherein R ^a and R ^b independently represent H; wherein said aryl, heterocyclyl, heteroaryl, C _3-6 cycloalkyl, C _3-6 cycloalkenyl are further optionally substituted with one or more substituents independently selected from halogen or halo-C _1-6 alkyl; and where R ⁵ is C _1-3 alkyl, halo-C _1-3 alkyl, or 4-6 membered heterocyclyl containing 1 heteroatom selected from oxygen; wherein heterocyclyl is optionally substituted with one substituent selected from halogen; or a pharmaceutically acceptable salt thereof; or a compound selected from the group consisting of 1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-benzyl-3-oxo-6-(2-azaspiro[3.3]heptan-2-yl)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-(2,2,2-trifluoroethoxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-benzyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(1-benzyl-6-oxo-3-((tetrahydro-2H-pyran-4-yl)oxy)-1,6-dihydropyridazin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-methyl-3-oxo-6-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydropyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4,4-difluorocyclohex-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4,4-difluorocyclohex-1-en-1-yl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; rac-9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one or (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac-9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; and (R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CH ₂ and R ² is F. 3. The compound of claim 1, wherein the compound is selected from 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(trifluoromethyl)benzo[d]oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(pyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-fluoro-6-(3-(trifluoromethyl)azetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(4-(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide; 9-(2-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-4-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(4-(5-azaspiro[2.3]hexan-5-yl)pyrimidin-2-yl)-1-(4-chloro-3-fluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-(3,3-dimethylazetidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-((1R,2R/1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-1,2,4-oxadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-hydroxy-3-(pyrrolidin-1-yl)-1,2,4-triazin-5-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(4-fluorophenyl)-4-methyl-3-oxo-3,4-dihydropyrazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-cyclopentyl-1,2,4-triazin-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(4-(trifluoromethyl)pyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(7-(trifluoromethyl)quinazolin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-(4-fluorophenyl)oxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-phenyl-2H-tetrazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-(3,3-difluoropyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-cyclohexyloxazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-(3-(trifluoromethyl)azetidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-(pyrrolidin-1-yl)-1,2,4-thiadiazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(1-(4-fluorophenyl)-1H-pyrazol-3-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(2-(4-fluorophenyl)-2H-1,2,3-triazol-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chlorophenyl)-9-(6-(4-fluorophenyl)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 2-(1-(4-chloro-3-fluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-4-(4-fluorophenyl)pyridine-1-oxide; 4-(3-chlorophenoxy)-2-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)pyridin-1-oxide; 9-(4-(4-amino-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(4-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-1,3,5-triazin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-5-fluoro-6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)pyridazin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-amino-2-(3-hydroxy-3-methylazetidin-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(1,4-oxazepan-4-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-methyl-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(1H-pyrazol-1-yl)pyrimidine-2-carbonitrile; 1-(3,4-difluorophenyl)-9-(2-methoxy-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(1H-pyrazol-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-morpholino-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(dimethylamino)-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4-chloro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-(4-fluoro-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-5-fluoro-6-(1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(4-amino-6-(4-fluoro-1H-pyrazol-1-yl)-1,3,5-triazin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(oxetan-3-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(oxazol-2-yl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(6-amino-2-(pyridin-2-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(4-(trifluoromethyl) -1H- pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one; rac -1-(3,4-difluorophenyl)-9-(2-(1-hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)1,9-diazaspiro[5.5]undecan-2-one; 4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-2-carboxamide; 9-(2-chloro-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-9-(2-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(4-chloro-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-(4-fluoro-1H-pyrazol-1-yl)-2-morpholinopyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(4,4-difluorocyclohex-1-en-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(4-fluorophenyl-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(perfluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(1,1,2,2-tetrafluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(hydroxyethyl)-6-(perfluoroethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(4-chloro-3-fluorophenyl)-9-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(4-propoxypyrimidin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one; rac -1-(3,4-difluorophenyl)-9-(6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-chloro-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-9-(2-amino-6-(2,2,2-trifluoro-1-(oxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(3,3-difluorocyclobutoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2,2,2-trifluoroethoxy-1,1-d2)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-isopropoxypyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2-hydroxyethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-(2,2,2-trifluoro-1-(3-methyloxetan-3-yl)ethoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(2,2,3,3,3-pentafluoropropoxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-((4,4-difluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-(((3S,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-((tetrahydro-2H-pyran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-((tetrahydro-2H-pyran-4-yl-4-d)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac-9-(2-amino-6-((3-methyltetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; rac -9-(2-amino-6-(((3S,4R)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; rac -1-(3,4-difluorophenyl)-9-(6-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; rac -1-(3,4-difluorophenyl)-9-(6-(((3R,4R)-4-fluorotetrahydrofuran-3-yl)oxy)-2-(hydroxymethyl)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; (S)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; rac -ethyl-4-(1-(3,4-difluorophenyl)-2-oxo-1,9-diazaspiro[5.5]undecan-9-yl)-6-(((3S,4S)-4-fluorotetrahydrofuran-3-yl)oxy)pyrimidine-2-carboxylate; (R)-9-(2-amino-6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; 1-(3,4-difluorophenyl)-9-(2-(hydroxymethyl)-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; ( S )-9-(2-amino-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-4-fluoro-1,9-diazaspiro[5.5]undecan-2-one; And 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 9-(2-amino-6-(4-(trifluoromethyl) -1H- pyrazol-1-yl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one; 9-(2-amino-6-(1,1-difluoroethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5.5]undecan-2-one and 9-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-1,9-diazaspiro[5,5]undecan-2-one. 5. The compound of claim 1, which is 1-(3,4-difluorophenyl)-9-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)-1,9-diazaspiro[5.5]undecan-2-one; or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, which is (R)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; or (S)-9-(2-amino-6-((1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)-1-(3,4-difluorophenyl)-3-oxa-1,9-diazaspiro[5.5]undecan-2-one; or a pharmaceutically acceptable salt thereof. 7. A method for modulating leukotriene C4 synthase (LTC4S) activity in a subject, wherein the method comprises administering to the subject a single dosage of 1-1000 mg for a subject weighing 50-70 kg, of a compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof.