Selective dual agonists of muscarinic 1 and 4 receptors and therapeutic uses thereof

Abstract

This application discloses oxime-substituted azabicyclic compounds as selective dual agonists of muscarinic 1 and 4 receptors, and pharmaceutical compositions, preparation methods, and therapeutic uses thereof, as medicaments for treatment of neuropsychiatric disorders associated with muscarinic 1 and / or muscarinic 4 receptors, such as schizophrenia, bipolar disorder, and related conditions.

Description

[0001]Docket No.: 367605.00005 SELECTIVE DUAL AGONISTS OF MUSCARINIC 1 AND 4 RECEPTORS AND THERAPEUTIC USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Application No. 63 / 647,346, filed on May 14, 2024, and Application No. 63 / 750,368, filed on January 28, 2025, the disclosures of both of which are incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure relates to selective dual agonists of muscarinic 1 and 4 receptors as therapeutic agents for treatments of schizophrenia, bipolar disorder, and related conditions such as, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders. BACKGROUND OF THE DISCLOSURE Schizophrenia is a severe mental disorder characterized by disturbances in thoughts, emotions, and perceptions. It is a global phenomenon, affecting people across cultures and socio-economic backgrounds. The World Health Organization (WHO) estimates that about 20 million people worldwide suffer from schizophrenia. Lifetime prevalence is estimated to be around 0.3-0.7% of the population. Symptoms typically emerge in late adolescence or early adulthood; however, affect individuals of any age. The subtle signs and symptoms may begin to emerge before the full onset of the disorder, a period referred to as the prodromal phase of schizophrenia. Schizophrenia is a complex mental disorder characterized by a range of symptoms that can be broadly categorized into positive, negative, and cognitive impairment symptom domains. Schizophrenia is associated with social dysfunction and sleep disturbances, and experience of depersonalization. The etiology of schizophrenia is complex, and the exact cause is not fully understood. It involves a combination of nature, nurture and triggering factors ranging from genetics with a polygenic nature, prenatal and perinatal complications, aberrant epigenetics, and interaction of genetic and environmental interactions, neuroimmune disfunctions, psychosocial dynamics, stressful life events, and substance use. The abnormalities at the molecular and cellular levels within the brain are conceptually the molecular pathology of schizophrenia, while the precise molecular mechanisms are not fully understood. Previous theories include dopamine dysregulation, glutamate dysfunction, and neurotransmitter imbalance; these are supported by Docket No.: 367605.00005 and inspired to develop newer typical and atypical antipsychotics and glutamatergic agents for schizophrenia. Newer theories include mitochondrial dysfunction, oxidative stress, and chronic inflammation and immune dysfunction. Brain structure abnormalities have been known to occur in schizophrenia, and more recently, the deficits in synaptic plasticity and excessive synaptic pruning have also been revealed. The first- and second-generations of antipsychotics primarily block dopamine D2 receptors in the brain. There is no interceptive treatment to prevent schizophrenia in the high- risk individuals such as those with signs of prodromal schizophrenia. Also, there is no effective treatment for CIAS. A large portion of patients become chronic schizophrenic despite the treatment effort. There are also portions of patients who do not respond to antipsychotics, a phenomenon known as treatment-resistant schizophrenia (TRS). Bipolar disorder, also known as manic-depressive illness, is a mental health condition characterized by extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). These mood episodes can significantly impact a person’s energy, activity levels, and ability to perform daily tasks. Bipolar disorder affects approximately 1–3% of the global population and most commonly develops in late adolescence or early adulthood (average onset: 18–25 years), although it can also emerge in childhood or later in life. The condition is associated with substantial direct costs, such as healthcare expenses for hospitalizations and medications, as well as indirect costs, including lost productivity and disability claims. In the U.S. alone, the annual economic costs of bipolar disorder are estimated to exceed $200 billion. The exact causes of bipolar disorder are not fully understood, but it is believed to result from a complex interplay of genetic, neurobiological, and environmental factors. Bipolar disorder has a strong hereditary component, with first-degree relatives of individuals with the condition being at 7–10 times higher risk. Neurobiological factors include neurotransmitters (glutamate, GABA, dopamine and serotonin, etc.) dysregulation, alterations in brain structure and connectivity, and mitochondrial dysfunction. Episodes of mania and depression can be triggered by environmental, psychosocial, and other factors, such as stressful or traumatic life events, substance use, and disruptions in sleep or circadian rhythms. The current treatment of bipolar disorder involves a combination of pharmacotherapy and psychotherapy. Pharmacological treatments include mood stabilizers, atypical antipsychotics (second-generation antipsychotics), antidepressants, and other agents. Notably, atypical antipsychotics are effective in treating acute mania, bipolar depression, and in the long- Docket No.: 367605.00005 term prevention of mood episodes. They are often combined with mood stabilizers, such as lithium or valproate, to achieve a synergistic effect. However, these medications can have potential side effects, including metabolic abnormalities, extrapyramidal symptoms, sedation, and prolactin elevation. Additionally, a significant portion of patients do not respond to current treatments. Schizophrenia and bipolar disorder share several overlapping clinical features, including the timing of disease onset, psychotic symptoms, cognitive dysfunction, and functional impairments. Both disorders can be effectively treated with atypical antipsychotics. While there are differences in the specifics, neurotransmitter dysregulation and alterations in regional brain structure and connectivity are observed in both conditions. Studies have shown a genetic correlation of approximately 0.60–0.70 between the two disorders, indicating a substantial shared genetic risk. Recent clinical trials have demonstrated the efficacy of certain agonists of M1 and M4 muscarinic receptors, i.e., KarXT (a combination of Xanomeline and Trospium), in treatment of schizophrenia (Kaul, I. et al. Lancet, 2024, 403, 160.). Preclinical studies have shown that the antipsychotic effects of Xanomeline are mediated by M1 and M4 receptors (Paul, S. M. et al. Am. J. Psychiatry, 2022, 179, 611. Paul, S. M. Bio. Psychiatry, 2024, 96, 627.). Xanomeline has also been shown to be effective in the amphetamine-induced hyperlocomotion model for schizophrenia (Stanhope, K. J. J. Pharmacol. Exp. Ther.2001, 299, 782), which is also used as a model for bipolar disorder (Chen, G. Mol. Psychiatry, 2010, 15, 883.). Additionally, studies have indicated the role of the M1 receptor in bipolar disorder (Creson, T. K. Bipolar Disord. 2011, 13, 238.). However, developments of new compounds as dual agonists of muscarinic 1 and 4 receptors and useful therapeutic agents of neuropsychiatric disorders such as schizophrenia bipolar disorder and related conditions are still urgently needed. SUMMARY OF THE DISCLOSURE The present disclosure provides oxime-substituted azabicyclic compounds as selective dual agonists of muscarinic 1 and 4 receptors for treatment of neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, such as schizophrenia, bipolar disorder, and related conditions including, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders. In one aspect, the present disclosure provides a method of treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering Docket No.: 367605.00005 to a subject in need thereof a therapeutically effective amount of a compound of Formula I: or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6alkyl and C1-6haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6 alkyl, deuterated C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 6-membered heterocyclyl, C6-10aryl, and 5- to 10-membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8 cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4alkyl, C1-4 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; R7at each occurrence is independently selected from H, deuterium, C1-6 alkyl, deuterated C1-6alkyl, and C1-6haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6 alkyl; and Docket No.: 367605.00005 Rcand Rdare independently H or C1-4 alkyl, with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) if m is 1, then R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) if m is 2, then the two R1are not both Cl, CF3, or OCH3. In another aspect, the present disclosure provides a compound of formula (I): or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6alkyl, C1-6haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6 alkyl and C1-6 haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 6-membered heterocyclyl, C6-10aryl, and 5- to 10-membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8 cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4 alkyl, C1- 4 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy; Docket No.: 367605.00005 R7at each occurrence is independently selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, and C1-6 haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6 alkyl; and Rcand Rdare independently H or C1-4 alkyl, with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) when m is 1, R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) when m is 2, the two R1are not both Cl, CF3, or OCH3. In another aspect, the present disclosure provides a compound of formula (II-1): or an isomer, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, 2, 3; n is 0 or 1; R1at each occurrence is independently selected from hydrogen, deuterium, chlorine, bromine, fluorine, OH, OCHF2, OCF3, CHF2, CF3, OMe, and OCD3; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1-4alkyl, and C1-4haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or -CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2); R5and R6are each independently hydrogen or deuterium; and R7is C1-4 alkyl or deuterated C1-4 alkyl; and wherein at least one of R1to R6is deuterium or comprises a deuterium substituent. Docket No.: 367605.00005 In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (II) or (III) according to any embodiments disclosed herein, or an isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides method for treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), or (III) according to any embodiment disclosed. In another aspect, the present disclosure provides a method for treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed. In another aspect, the present disclosure provides use of a compound of formula (I), (II), or (III) according to any embodiment disclosed, or an isomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a neuropsychiatric disorder. Other aspects and advantages of the present disclosure can be better understood through the following drawings, detailed description, examples, and claims. DETAILED DESCRIPTION OF THE DISCLOSURE In one aspect, the present disclosure provides a method of treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; Docket No.: 367605.00005 R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6alkyl and C1-6haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6 alkyl, deuterated C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 6-membered heterocyclyl, C6-10aryl, and 5- to 10-membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8 cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4alkyl, C1-4 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy; R7at each occurrence is independently selected from H, deuterium, C1-6 alkyl, deuterated C1-6alkyl, and C1-6haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6 alkyl; and Rcand Rdare independently H or C1-4 alkyl, with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) when m is 1, R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) when m is 2, the two R1are not both Cl, CF3, or OCH3. In some embodiments of this aspect, the ring Ar in the compound of Formula (I) is selected from: Docket No.: 367605.00005 In some embodiments, the ring Ar in the compound of Formula (I) is selected from: m is 0, 1, or 2; R1ais hydrogen or C1-4 alkyl; R1at each occurrence is independently hydrogen, deuterium, halogen, C1-4alkyl, C1-4haloalkyl, CN, OR7; R3and R4are independently selected from C1-4 alkyl, deuterated C1-4 alkyl, C1-4 haloalkyl, C3-6cycloalkyl, and phenyl; or R3and R4together with the carbon atom to which they are attached form C3-6cycloalkyl or 3- to 6-membered heterocyclyl; and R7at each occurrence is independently selected from H, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl. In some embodiments of this aspect, the compound of Formula (I) is a compound of formula (II): Docket No.: 367605.00005 wherein m, n, and R1to R6are each as defined in any of the foregoing embodiments of Formula (I). In some embodiments, the compound of formula (I) or (II) is a compound of formula (II-1): or an isomer, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, 2, or 3; n is 0 or 1; R1at each occurrence is independently selected from hydrogen, deuterium, chlorine, bromine, fluorine, OH, OCHF2, OCF3, CHF2, CF3, OMe, and OCD3; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or -CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2); R5and R6are each independently hydrogen or deuterium; and R7is C1-4alkyl or deuterated C1-4alkyl. In some embodiments, the compound of formula (II) or (II-1) is selected from Docket No.: 367605.00005 In some embodiments, the compound of formula (II) or (II-1) is , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) or (II-1) is , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) or (II-1) is , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) or (II-1) is Docket No.: 367605.00005 , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) or (II-1) is , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (II) or (II-1) is , or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments of this aspect, the compound of formula (I) or (II) is selected from: Docket No.: 367605.00005 or an isomer, or a pharmaceutically acceptable salt thereof. In some embodiments of this aspect, the neuropsychiatric disorder is selected from schizophrenia, mania, bipolar disorder, and related conditions including, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders. In another aspect, the present disclosure provides a compound of formula (I): Docket No.: 367605.00005 or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6alkyl and C1-6haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-10 aryl, and 5- to 10-membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4alkyl, C1-4haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy; R7at each occurrence is independently selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, and C1-6 haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6 alkyl; and Rcand Rdare independently H or C1-4 alkyl, Docket No.: 367605.00005 with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) when m is 1, R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) when m is 2, the two R1are not both Cl, CF3, or OCH3. In some embodiments of this aspect, the ring Ar in the compound of Formula (I) is selected from: In some embodiments, the ring Ar in the compound of Formula (I) is selected from: m is 0, 1, or 2; R1ais hydrogen or C1-4 alkyl; R1at each occurrence is independently hydrogen, deuterium, halogen, C1-4alkyl, C1-4haloalkyl, CN, OR7; and Docket No.: 367605.00005 R7at each occurrence is independently selected from H, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl. In some embodiments of this aspect, the compound of Formula (I) is a compound of formula (II): wherein m, n, and R1to R6are each as defined in any of the foregoing embodiments of Formula (I). In some embodiments of this aspect, the compound of formula (I) or (II) is selected from: Docket No.: 367605.00005 or an isomer, or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a compound of formula (II-1): or an isomer, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, 2, 3; n is 0 or 1; Docket No.: 367605.00005 R1at each occurrence is independently selected from hydrogen, deuterium, chlorine, bromine, fluorine, OH, OCHF2, OCF3, CHF2, CF3, OMe, and OCD3; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1-4alkyl, and C1-4haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or -CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2); R5and R6are each independently hydrogen or deuterium; and R7is C1-4alkyl or deuterated C1-4alkyl; and wherein at least one of R1to R6is deuterium or comprises a deuterium substituent. In some embodiments, the compound of formula (II-1) is a compound of formula III: wherein: R1at each occurrence is independently hydrogen or deuterium; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or -CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2); and R7is C1-4 alkyl or deuterated C1-4 alkyl; and wherein at least one of R1, R3, and R4, is deuterium, or R7is deuterated C1-4alkyl. In some embodiments, the compound of formula (II-1) or (III) is selected from: Docket No.: 367605.00005 In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (II), (II-1), or (III) according to any embodiments disclosed herein, or an isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides method for treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II-1), or (III) according to any embodiment disclosed. In another aspect, the present disclosure provides a method for treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed. In another aspect, the present disclosure provides use of a compound of formula (I), (II), (II-1), or (III) according to any embodiment disclosed, or an isomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is selected from schizophrenia, mania, bipolar disorder, and related conditions including, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders. In addition, any reasonable combinations of the embodiments disclosed as apparent to those of ordinary skill in the art are also encompassed by the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Docket No.: 367605.00005 The term “alkyl" refers to a branched or unbranched monovalent aliphatic hydrocarbon radical derived from an alkane containing 1 to 12 carbon atoms by removal of one hydrogen atom. In certain embodiments, an alkyl group contains 1 to 10 carbons. In certain embodiments, an alkyl group contains 1 to 8 carbons. In certain embodiments, sometimes preferably, an alkyl group contains 1 to 6 carbons, and in certain embodiments, sometimes more preferably, an alkyl group contains 1 to 4 carbons. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or the like, and their isomeric counterparts. The alkyl group can be substituted or unsubstituted. The term "cycloalkyl" refers to any univalent radical formed by removal of one hydrogen atom from a cycloalkane. In certain embodiments, cycloalkyl group contains 3 to 10 carbons. In certain embodiments, cycloalkyl group contains 3 to 8 carbons. In certain embodiments, sometimes preferably, cycloalkyl group contains 3 to 6 carbons. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The cycloalkyl can be substituted or unsubstituted. The term "heterocyclyl" refers to a monocyclic or polycyclic non-aromatic carbocycle radical containing at least one heteroatom (N, O, and / or S) in the ring. At least one ring in the heterocyclyl ring system is non-aromatic, and it can have any degree of saturation. The heteroatom can be located on the non-aromatic or aromatic ring of a heterocyclyl group. The heterocyclyl can have 3 to 14, sometimes preferably 3 to 10, ring atoms (i.e., the number of atoms constituting the ring skeleton, including the number of carbon atoms and heteroatoms). Sometimes a heterocyclyl group may preferably be a 3-, 4-, 5-, 6-, or 7-membered monocyclic group, and sometimes a heterocyclyl preferably may preferably be a 8-, 9, or 10-membered bicyclic group. Examples of heterocyclyl include, but not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thietanyl, piperidinyl, piperazinyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3- dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,4-oxathianyl , 2H-1,3- dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, oxazolidinone, thiazolidinyl, 1,3-oxathiolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinolinyl. Docket No.: 367605.00005 The term “aryl” refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi- electron system. Preferably aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl group can be substituted or unsubstituted. The term “heteroaryl” refers to a 5 to 14 membered aryl system having 1 to 4 heteroatom(s) selected from O, S and N as ring atoms. Preferably a heteroaryl is 5- to 10- membered (such as 5, 6, 7, 8, 9 and 10 membered), more preferably 5- or 6- membered, for example, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, oxadiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, benzothienyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. The heteroaryl group can be substituted or unsubstituted. The term “alkoxy” refers to both an -O-(alkyl), for example, methoxy, ethoxy, propoxy, butoxy, and the like. The term “bond” refers to a covalent bond using a sign of “-”. The term “hydroxyl” refers to an -OH group. The term “halogen” or “halo” refers to fluoro, chloro, bromo or iodo atoms. The term “amino” refers to a -NH2group. The term "alkylthio" refers to alkyl-S-. The term “cyano” refers to a -CN group. The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, wherein the halogen atoms can be the same or different. The term “nitro” refers to a -NO2 group. The term “oxo group” refers to a =O group. The term “carboxyl” refers to a -C(O)OH group. The term “alkoxycarbonyl” refers to a -C(O)O(alkyl) group. The term “alkylcarbonyl” refers to a -C(O)-alkyl group. Docket No.: 367605.00005 The term “optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in which the event or circumstance may or may not occur. The term “substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atom(s), independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable. As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. The terms “a”, “an” and “the”, or similar references, in the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like. A “pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present disclosure or physiologically / pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. “Pharmaceutically acceptable salts” refer to salts of the compounds of the disclosure, such salts being safe and effective when used in a mammal and have corresponding biological Docket No.: 367605.00005 activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Pharmaceutically acceptable salts are well known in the art. See, e.g., S. M. Berge et al., J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide as well as organic acids, such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and related inorganic and organic acids. Preferred pharmaceutically acceptable salts include hydrochloride or hydrobromide salts. Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine. When it is possible that, for use in therapy, therapeutically effective amounts of a compound of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the disclosure further provides pharmaceutical compositions, which include any compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and one or more, preferably one to three, pharmaceutically acceptable carriers, diluents, or other excipients. The carrier(s), diluent(s), or other excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the subject being treated. Docket No.: 367605.00005 In the compounds disclosed herein, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. For example, substitution with heavier isotopes, such as replacing hydrogen (H) with deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half- life or reduced dosage requirements) and hence may be preferred in some circumstances. In addition, certain isotopically-labeled compounds (e.g., with3H and14C) are useful in compound and / or substrate tissue distribution assays. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The present invention is meant to encompass all suitable isotopic variations of the compounds disclosed. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Typically, the pharmaceutical compositions of this disclosure will be administered from once every 1 to 5 days to about 1-5 times per day, or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example, by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred. Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in Docket No.: 367605.00005 aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present. Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added. Docket No.: 367605.00005 Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release, for example, by coating or embedding particulate material in polymers, wax, or the like. It should be understood that, in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The term “subject,” “patient,” or the like, includes both humans and other mammalian animals, especially primates, preferably humans. The term “therapeutically effective amount" refers to an amount of a compound or composition that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. A "therapeutically effective amount" can vary depending on, inter alia, the compound, the disease and its severity, and the age, weight, or other factors of the subject to be treated. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The term “treat”, “treating”, “treatment”, or the like, refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and / or condition. In addition, the compounds of present disclosure may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and / or condition but has not yet been diagnosed as having it. The following non-limiting examples further illustrate certain aspects of the present disclosure. List of chemical abbreviations DCM: Dichloromethane DEAD: Diethyl azodicarboxylate DMF: Dimethylformamide ESI: Electrospray Ionization Et2O: Ethyl ether Docket No.: 367605.00005 Et3N: Triethylamine (TEA) EtOAc: Ethyl acetate EtOH: Ethanol HPLC: High-performance liquid chromatography HRMS: High resolution mass spectrometry MeOH: Methanol mm: Millimeter MS: Mass spectrometry nm: Nanometer NMR: Nuclear Magnetic Resonance THF: Tetrahydrofuran TsCl: 4-Toluenesulfonyl chloride UV:"Ultraviolet μm: Micrometer SYNTHETIC METHODS AND EXAMPLES 1. Preparation of Compounds 1-8 Compound 1 through Compound 8 were prepared by following the general synthesis Scheme 1. --Scheme 1 Docket No.: 367605.00005 (Z)-1-azabicyclo[2.2.1]heptan-3-one oxime: To a solution of 1-azabicyclo[2.2.1]heptan-3- one (3.00 g, 26.99 mmol, 1.0 eq) in MeOH (50 mL), Et3N (2.73 g, 26.99 mmol, 1.0 eq) and NH2OH•HCl (3.75 g, 53.98 mmol, 2.0 eq) were added at 25 °C. The reaction mixture was stirred at 25 °C for 16 hrs. After the rection was complete, the solution was concentrated and the residue was partitioned between saturated K2CO3aqueous solution (100 mL) and DCM (100 mL). The organic phase was separated and concentrated to afford (Z)-1- azabicyclo[2.2.1]heptan-3-one oxime (1.85 g, 14.6 mmol, 54.3%) as a yellow solid. Rf (10:1 DCM:MeOH) = 0.32. 3-(3-Methoxyphenyl)prop-2-yn-1-ol: To a solution of 1-bromo-3-methoxybenzene (5.00 g, 26.73 mmol, 1.0 eq) in toluene (50 mL), propargyl alcohol (2.24 g, 40.10 mmol, 1.5 eq)，Et3N (2.70 g, 26.73 mmol, 1.0 eq), Pd(PPh3)4 (2.23 g, 3.20 mmol, 0.12 eq) and CuI (254 mg, 1.33 mmol, 0.05 eq) were added at 25 °C. The reaction mixture was stirred at 80 °C for 16 hrs. After the reaction was complete, the mixture was cooled to 25 °C and filtrated through celite. The filtrate was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer was concentrated to afford 3-(3-methoxyphenyl)prop-2-yn-1-ol (2.50 g, 15.41 mmol, 57.6%) as a yellow oil. Rf(2:1 Petroleum ether:EtOAc) = 0.24. 3-(3-Methoxyphenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate: To a solution of 3-(3- methoxyphenyl)prop-2-yn-1-ol (0.1 g, 616 μmol,1 eq) in Et2O (50 mL), TsCl (141 mg, 739 μmol, 1.2 eq) and KOH (164 mg, 2.92 mmol, 4.75 eq) were added at 0 °C. The mixture was stirred at 0 °C for 4 hrs. After the rection was complete, the mixture was poured into ice water (100 mL). Et2O (100 mL x 2) was used to extract the product and the combined organic layer were concentrated to afford 3-(3-methoxyphenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate (0.18 g, 568.9μmol, 92.3%) as a red oil. Rf(3:1 Petroleum ether:EtOAc) = 0.55. Docket No.: 367605.00005 (R,S)-(±)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxyphenyl)prop-2-yn-1-yl) oxime: To a solution of NaH (31.70 mg, 792.6 μmol, 60% purity, 1.0 eq) in DMF (10 mL), (Z)-1-azabicyclo[2.2.1]heptan-3-one oxime (0.1 g, 792 μmol, 1.0 eq) was added at 0 °C and then a solution of 3-(3-methoxyphenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate (253 mg, 800 μmol, 1.01 eq) in DMF (5 mL) was added dropwise. The rection mixture was stirred at 25 °C for 16 hrs. After the reaction is complete, the reaction mixture was poured into ice water (50 mL). The aqueous layer was extracted with EtOAc (50 mL*2) and the combined organic layers were concentrated to afford the crude product. Rf(1:1 Petroleum ether:EtOAc) = 0.52. The crude product was purified by prep-HPLC and chiral SFC to afford Compound 1 (0.040 g, 20% yield) and Compound 2 (0.039 g, 20% yield). Both are yellow, oily solid. Example 1 Compound 1, (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxyphenyl)prop- 2-yn-1-yl) oxime: 96.1% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 96.9% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm). Optical rotation [α]D25= - 2.1 (methanol; c < 0.2 g / 100mL, low solubility);1H NMR (400 MHz; MeOH-d4) δ 7.25 (t, 1H, J = 7.7 Hz), 7.10-6.90 (m, 3H), 4.89 (s, 2H), 3.79 (s, 3H), 3.60-3.20 (m, 3H), 2.60-2.30 (m, 4H), 2.0-1.8 (m, 1H), 1.7-1.60 (m, 1H). MS-ESI (m / z): [M+H]+= 271.10. Example 2 Compound 2, (S)-(+)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxyphenyl)prop- 2-yn-1-yl) oxime: 96.0% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.2% Docket No.: 367605.00005 er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm). Optical rotation [α]D25= + 36 (methanol; c = 0.2 g / 100mL);1H NMR (400 MHz; Acetonitrile-d3) δ 7.30 (t, 1H, J = 7.7 Hz), 7.10-6.90 (m, 3H), 4.85 (s, 2H), 3.76 (s, 3H), 3.60-3.20 (m, 3H), 2.60-2.30 (m, 4H), 2.0-1.9 (m, 1H), 1.90-1.70 (m, 1H). MS-ESI (m / z): [M+H]+= 271.10. Compound 3-IM1 Compound 3-IM2 Compound 3-IM3 Compound 3-IM2, 3-(3-methoxyphenyl)prop-2-yn-1,1-d2-1-ol: To a solution of methyl 3- (3-methoxyphenyl)propiolate (5.55 g, 29.18 mmol, 1.0 eq) in Et2O (60 mL), LiAlD4 (735 mg, 17.50 mmol, 0.6 eq) was added slowly at 0 °C. The reaction mixture was stirred at 25 °C for 1 hrs. After the reaction was complete, the reaction mixture was cooled to 0 °C, and H2O (1 mL), NaOH (15%, 1 mL), H2O (1 mL) were added sequentially. The mixture was filtered and the filtrate was concentrated at 45 °C. The residue was purified via column chromatography (Petroleum ether:EtOAc=5:1) to afford Compound 3-IM2, 3-(3-methoxyphenyl)prop-2-yn- 1,1-d2-1-ol (3.30 g, 20.09 mmol, 68.8% yield) as a yellow oil. Rf (1:1 Petroleum ether:EtOAc) = 0.36.1H NMR (400 MHz; CDCl3) δ 7.25 (t, 1H, J = 7.7 Hz), 7.10-6.80 (m, 3H), 3.81 (s, 3H), 2.02 (br. S, 1H). Compound 3-IM3, 3-(3-methoxyphenyl)prop-2-yn-1-yl-1,1-d24-methylbenzenesulfonate: To a solution of Compound 3-IM2, 3-(3-methoxyphenyl)prop-2-yn-1,1-d2-1-ol (510 mg, 3.10 mmol, 1.0 eq) in Et2O (30 mL), TsCl (710 mg, 3.72 mmol, 1.2 eq) and KOH (827 mg, 14.75 mmol, 4.75 eq) were added sequentially at 0 °C. The reaction mixture was stirred at 0 °C for 4 hrs. After the reaction is complete, the reaction mixture was poured into ice water (100 mL). The aqueous layer was extracted with Et2O (100 mL*2). The combined organic layers were concentrated to afford Compound 3-IM3, 3-(3-methoxyphenyl)prop-2-yn-1-yl-1,1-d24- methylbenzenesulfonate (0.65 g, 2.04 mmol, 65.7%) as a red oil. Rf (3:1 Petroleum ether:EtOAc) = 0.55. Docket No.: 367605.00005 Compound 3, (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxyphenyl)prop- 2-yn-1-yl-1,1-d2) oxime: 96.6% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.1% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; acetonitrile-d3) δ 7.25 (t, 1H, J = 7.7 Hz), 7.10- 6.90 (m, 3H), 3.80 (s, 3H), 3.60-3.40 (m, 3H), 3.40- 3.20 (m, 4H), 2.10-1.7 (m, 2H). MS-ESI (m / z): [M+H]+= 273.20. D2 / H ratio by HRMS: 99.5%. Example 4 Compound 4, (S)-(+)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxyphenyl)prop- 2-yn-1-yl-1,1-d2) oxime: 96.6% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.1% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; DMSO-d6) δ 7.29 (t, 1H, J = 7.7 Hz), 7.04-6.98 (m, 3H), 3.76 (s, 3H), 3.60-3.40 (m, 3H), 3.40- 3.20 (m, 4H), 2.0-1.8 (m, 1H), 1.6-1.5 (m, 1H). MS-ESI (m / z): [M+H]+= 273.20. D2 / H ratio by HRMS: 99.1%. Compound 5-IM1, 1-bromo-3-(methoxy-d3)benzene: To a solution of 3-bromophenol (10.00 g, 57.80 mmol, 1.0 eq) and K2CO3 (11.98 g, 86.70 mmol, 1.5 eq) in DMF (100 mL),CD3I(16.75 g, 115.60 mmol, 2.0 eq) was added dropwise at 0 °C. The reaction mixture was then stirred at 25 °C for 2 hrs. After the rection was complete, the mixture was partitioned between H2O (200 mL) and EtOAc (200 mL). The organic layer was washed with brine (100 mL x 3), dried over MgSO4, filtered, concentrated to afford Compound 5-IM1, 1-bromo-3-(methoxy- d3)benzene (5.00 g, 26.30 mmol, 45.5%) as a yellow oil. Rf(2:1 Petroleum ether:EtOAc) = 0.53.1H NMR (400 MHz; CDCl3) δ 7.30-7.08 (m, 3H), 6.88-6.84 (m, 1H). Docket No.: 367605.00005 Compound 5-IM2, 3-(3-(methoxy-d3)phenyl)prop-2-yn-1-ol: To a solution of Compound 5-IM1, 1-bromo-3-(methoxy-d3)benzene (5.00 g, 26.30 mmol, 1.0 eq) in toluene (100 mL),propargyl alcohol (1.62 g, 28.93 mmol, 1.1 eq)� Et3N (10.64 g, 105.23 mmol, 4.0 eq),Pd(PPh3)4 (923 mg, 1.31 mmol, 0.05 eq) and CuI (510 mg, 2.63 mmol, 0.1 eq) were added at 25 °C. The reaction mixture was stirred at 80 °C for 16 hrs. After the rection was complete, the reaction mixture was cooled to 25 °C, and filtered through celite. The filtrate was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer were concentrated and the residue was purified via column chromatography (Petroleum ether:EtOAc=5:1) to afford Compound 5-IM2, 3-(3-(methoxy-d3)phenyl)prop-2-yn-1-ol (2.50 g, 15.13 mmol, 57.5%) as a yellow oil. Rf (2:1 Petroleum ether:EtOAc) = 0.24. Compound 5-IM3, 3-(3-(methoxy-d3)phenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate: To a solution of Compound 5-IM2, 3-(3-(methoxy-d3)phenyl)prop-2-yn-1-ol (200 mg, 1.21 mmol, 1.0 eq) in Et2O (30 mL), TsCl (276 mg, 1.45 mmol, 1.2 eq) and Et3N (581 mg, 5.75mmol, 4.75 eq) were added at 0 °C. The reaction mixture was stirred at 0 °C for 4 hrs. After the reaction was complete, the reaction mixture was poured into ice water (100 mL). The aqueous layer was extracted with Et2O (100 mL*2) and the combined organic layers were concentrated to afford Compound 5-IM3, 3-(3-(methoxy-d3)phenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate (300 mg, 939.2�mol, 77.5%) as a red oil. Rf (3:1 Petroleum ether:EtOAc) = 0.55. Compound 5, (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxy-d3)- phenyl)prop-2-yn-1-yl) oxime: 95.3% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 97.2% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; Acetonitril-d3) δ 7.35(t, 1H, J = 7.7 Hz), 7.04-6.90 (m, 3H), 4.82 (s, 2H), 3.50-3.00 (m, 5H), 2.5-2.2 (m, 2H), 2.0-1.9 (m, 1H), 1.7- 1.6 (m, 1H).4.00-3.60 (m, 1H), 3.50-3.00 (m, 5H), 2.60-1.80 (m, 3H). MS-ESI (m / z): [M+H]+= 274.10. D3 / H ratio by HRMS: 100%. Example 6 Compound 6, (S)-(+)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxy-d3)- phenyl)prop-2-yn-1-yl) oxime: 97.6% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.2% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 Docket No.: 367605.00005 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; MeOH-d4) δ 7.25 (t, 1H, J = 7.7 Hz), 7.04-6.90 (m, 3H), 4.82 (s, 2H), 3.7-3.2 (m, 3H), 3.1-2.6 (m, 4H), 2.0-1.9 (m, 1H), 1.7- 1.6 (m, 1H). MS-ESI (m / z): [M+H]+= 274.20. D3 / H ratio by HRMS: 100%. Example 7 Compound 5-IM1 Compound 7-IM2Compound 7-IM3 Compound 7-IM4Compound 7-IM2, 1-bromo-3-(methoxy-d3)benzene-2,4,6-d3: Compound 5-IM1, 1- bromo-3-(methoxy-d3)benzene (5.00g, 26.30 mmol, 1.0 eq) was added into DCl (30 mL，20% purity, 5.0eq) and the reaction mixture was stirred at 100 °C for 30 hrs. The mixture was cooled to 25 °C and extracted with EA (50 mL*2). The combined organic layers were concentrated to afford the crude residue. The above operation was repeated three times until HNMR showed complete deuterium exchange to afford Compound 7-IM2, 1-bromo-3-(methoxy-d3)benzene- 2,4,6-d3, (2.10 g, 10.9 mmol, 41%). As a red oil.1H NMR (400 MHz; CDCl3) δ 7.16 (s, 1H). Compound 7-IM3, 3-(3-(methoxy-d3)phenyl-2,4,6-d3)prop-2-yn-1-ol: To a solution of Compound 7-IM2, 1-bromo-3-(methoxy-d3)benzene-2,4,6-d3(2.00 g, 10.35 mmol, 1.0 eq) in toluene (50 mL), propargyl alcohol (638 mg, 11.39 mmol, 1.1 eq)，Et3N (4.19 g, 41.43 mmol, 4.0 eq), Pd(PPh3)4(363 mg, 0.51 mmol, 0.05 eq) and CuI (197 mg, 1.03 mmol, 0.1 eq) were added at 25 °C. The reaction mixture was stirred at 80 °C for 16 hrs. After the reaction was complete, the mixture was cooled to 25 °C and filtered through celite. The filtrate was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer were concentrated and the residue was purified via column chromatography (Petroleum ether:EtOAc=5:1) to afford Compound 7-IM3, 3-(3-(methoxy-d3)phenyl-2,4,6-d3)prop-2-yn-1-ol (940 mg, 5.61 mmol, 54.1%) as a yellow oil. Rf(2:1 Petroleum ether:EtOAc) = 0.24. Compound 7-IM4, 3-(3-(methoxy-d3)phenyl-2,4,6-d3)prop-2-yn-1-yl 4- methylbenzenesulfonate: To a solution of Compound 7-IM3, 3-(3-(methoxy-d3)phenyl- 2,4,6-d3)prop-2-yn-1-ol (200 mg, 1.21 mmol, 1.0 eq) in Et2O (30 mL), TsCl (276 mg, 1.45 mmol, 1.2 eq) and Et3N (581 mg, 5.75mmol, 4.75 eq) were added at 0 °C. The reaction mixture Docket No.: 367605.00005 was stirred at 0 °C for 4 hrs. After the reaction was complete, the reaction mixture was poured into ice water (100 mL). The aqueous layer was extracted with Et2O (100 mL*2) and the combined organic layers were concentrated to afford Compound 7-IM4, 3-(3-(methoxy- d3)phenyl-2,4,6-d3)prop-2-yn-1-yl 4-methylbenzenesulfonate (288 mg, 901.7 μmol, 74.4%) as a red oil. Rf(3:1 Petroleum ether:EtOAc) = 0.55. Compound 7, (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxy-d3)phenyl- 2,4,6-d3)prop-2-yn-1-yl) oxime: 95.1% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 97.9% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; Acetonitrile-d3) δ 7.29 (s, 1H), 4.86 (s, 2H), 3.60-3.20 (m, 3H), 2.7-2.2 (m, 4H), 2.1-1.8 (m, 2H). MS-ESI (m / z): [M+H]+= 277.20. D6 / H ratio by HRMS: 100%. Example 8 Compound 8, (S)-(+)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methoxy-d3)phenyl- 2,4,6-d3)prop-2-yn-1-yl) oxime: 97.2% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.3% er (er measured with chiral HPLC, column: Diacel Chiralpak AD, 250 × 46 mm,10 μm; UV detection at 254 nm).1H NMR (400 MHz; Acetonitrile-d3) δ 7.28 (s, 1H), 4.86 (s, 2H), 3.60-3.20 (m, 3H), 2.7-2.2 (m, 4H), 2.1-1.8 (m, 2H). MS-ESI (m / z): [M+H]+= 277.20. D6 / H ratio by HRMS: 98.8%. 2. Preparation of Compounds 9-33 I Ar Pd(PPh3)4, CuITEA a (R)-(-)-Z-isomer Scheme 2 Docket No.: 367605.00005 Compound 9 through Compound 33 were prepared by following the general synthesis Scheme 2 (References: Tecle, H., et al., Bioorg. Med. Chem. Lett.1995, 5, 631; WO98 / 32759, and WO95 / 34562). Z / E (Z / E)-1-azabicyclo[2.2.1]heptan-3-one oxime: To a solution of (R)-1- azabicyclo[2.2.1]heptan-3-one (3.00 g, 27.0 mmol, 1.0 equiv., >98% er) in MeOH (50 mL), Et3N (2.73 g, 27.0 mmol, 1.0 equiv.) and NH2OH•HCl (3.75 g, 54.0 mmol, 2.0 equiv.) were added at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. After the rection was complete, the solution was concentrated and the residue was partitioned between saturated K2CO3 aqueous solution (100 mL) and DCM (100 mL). The organic phase was separated and concentrated to afford (Z / E = ~1.6:1)-(R)-1-azabicyclo[2.2.1]heptan-3-one oxime (1.85 g, 14.6 mmol, 54.3%) as a yellow solid. 3-(2-Fluoro-3-methoxyphenyl)prop-2-yn-1-ol: To a solution of 1-Iodo-2-fluoro-3- methoxybenzene (6.7 g, 26.7 mmol, 1.0 equiv.) in toluene (50 mL), propargyl alcohol (2.24 g, 40.1 mmol, 1.5 equiv.)，Et3N (2.70 g, 26.7 mmol, 1.0 equiv.), Pd(PPh3)4 (2.23 g, 3.20 mmol, 0.12 equiv.) and CuI (254 mg, 1.33 mmol, 0.05 equiv.) were added at 25 °C. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was complete, the mixture was cooled to 25 °C and filtrated through celite. The filtrate was partitioned between H2O (100 mL) and EtOAc (100 mL). The organic layer was concentrated to afford 3-(2-fluoro-3- methoxyphenyl)prop-2-yn-1-ol (2.77 g, 15.4 mmol, 57.6%) as a yellow oil. 3-(2-Fluoro-3-methoxyphenyl)prop-2-yn-1-yl 4-methylbenzenesulfonate: To a solution of 3-(2-fluoro-3-methoxyphenyl)prop-2-yn-1-ol (0.11 g, 0.61 mmol, 1.0 equiv.) in Et2O (50 mL), TsCl (141 mg, 0.74 mmol, 1.2 equiv.) and KOH (164 mg, 2.92 mmol, 4.75 equiv.) were added at 0 °C. The mixture was stirred at 0 °C for 4 hours. After the rection was complete, the mixture was poured into ice water (100 mL). Et2O (100 mL*2) was used to extract the product and the Docket No.: 367605.00005 combined organic layers were concentrated to afford 3-(2-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl 4-methylbenzenesulfonate (0.18 g, 0.55 mmol, 90%) as an oil. (R)-(-)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(2-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime: To a solution of NaH (31.70 mg, 0.79 mmol, 60% purity, 1.0 equiv.) in DMF (10 mL), (Z / E, ~1.6:1)-1-azabicyclo[2.2.1]heptan-3-one oxime (0.1 g, 0.79 mmol, 1.0 equiv.) was added at 0 °C and then a solution of 3-(2-fluoro-3-methoxyphenyl)prop-2-yn-1-yl 4- methylbenzenesulfonate (267 mg, 0.80 mmol, 1.01 equiv.) in DMF (5 mL) was added dropwise. The rection mixture was stirred at 25 °C for 16 hours. After the reaction is complete, the reaction mixture was poured into ice water (50 mL). The aqueous layer was extracted with EtOAc (50 mL*2) and the combined organic layers were concentrated to afford the crude product as a Z / E mixture. The pure Z-isomer was isolated via preparative HPLC. Example 9 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(2-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (9): 97.4% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 289.40.1H NMR (METHANOL-d4, 400 MHz) δ 7.0-7.1 (m, 2H), 7.0-7.0 (m, 1H), 4.81 (s, 2H), 3.88 (s, 3H), 3.4-3.5 (m, 1H), 3.4-3.4 (m, 1H), 3.20 (d, 1H, J=4.3 Hz), 2.9-3.0 (m, 1H), 2.79 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6- 1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -134.4 (s). Example 10 Docket No.: 367605.00005 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(2-chloro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (10): 98.5% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.4% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). Optical rotation [α]D25= - 6.7 (methanol; c = 0.2 g / 100 mL). MS-ESI (m / z): [M+H]+= 305.30.1H NMR (METHANOL-d4, 400 MHz) δ 7.25 (t, 1H, J=7.9 Hz), 7.09 (d, 2H, J=8.1 Hz), 4.8 (s, 2H), 3.90 (s, 3H), 3.52 (br d, 1H, J=16.1 Hz), 3.33-3.35 (m, 1H), 3.2-3.3 (m, 1H), 3.00 (br s, 1H), 2.83 (br d, 1H, J=9.5 Hz), 2.6-2.8 (m, 2H), 2.0-2.1 (m, 1H), 1.68 (br t, 1H, J=11.7 Hz). Example 11 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(2-methyl-3-methoxyphenyl)prop-2- yn-1-yl) oxime (11): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.8% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). Optical rotation [α]D25= - 9.7 (methanol; c = 0.2 g / 100 mL). MS-ESI (m / z): [M+H]+= 285.40.1H NMR (METHANOL-d4, 400 MHz) δ 7.1-7.1 (m, 1H), 6.99 (d, 1H, J=6.8 Hz), 6.93 (d, 1H, J=8.3 Hz), 4.8-4.9 (s, 2H), 3.83 (s, 3H), 3.4-3.5 (m, 1H), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.9-3.0 (m, 1H), 2.80 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.29 (s, 3H), 2.0-2.2 (m, 1H), 1.6-1.7 (m, 1H). Example 12 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (12): 98.0% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.4% Docket No.: 367605.00005 Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 289.12.1H NMR (METHANOL-d4, 400 MHz) δ 7.16 (dd, 1H, J=1.3, 8.2 Hz), 7.0-7.1 (m, 2H), 4.80 (s, 2H), 3.87 (s, 3H), 3.4-3.5 (m, 1H), 3.3-3.4 (m, 1H), 3.20 (br d, 1H, J=3.7 Hz), 2.97 (m, 1H), 2.79 (br d, 1H, J=8.8 Hz), 2.6-2.7 (m, 2H), 2.03 (br t, 1H, J=11.0 Hz), 1.65 (br s, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -134.8 (s). Example 13 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(6-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (13): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.2% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 289.12.1H NMR (METHANOL-d4, 400 MHz) δ 7.06 (t, 1H, J=9.0 Hz), 6.9-7.0 (m, 2H), 4.84 (s, 2H), 3.78 (s, 3H), 3.4-3.6 (m, 1H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.9-3.1 (m, 1H), 2.82 (br d, 1H, J=9.3 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.67 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -123.6 (s). Example 14 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(5-fluoro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (14): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 289.12.1H NMR (METHANOL-d4, 400 MHz) δ 6.82 (s, 1H), 6.7- 6.8 (m, 2H), 4.81 (s, 2H), 3.81 (s, 3H), 3.4-3.6 (m, 1H), 3.3-3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.9- 3.1 (m, 1H), 2.80 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -113.6 (s). Example 15 Docket No.: 367605.00005 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-chloro-3-methoxyphenyl)prop-2-yn- 1-yl) oxime (15): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.7% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 305.34.1H NMR (METHANOL-d4, 400 MHz) δ 7.33 (d, 1H, J=8.1 Hz), 7.12 (d, 1H, J=1.5 Hz), 7.00 (dd, 1H, J=1.7, 8.1 Hz), 4.81 (s, 2H), 3.89 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.79 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 16 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-methyl-3-methoxyphenyl)prop-2- yn-1-yl) oxime (16): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.6% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 285.40.1H NMR (METHANOL-d4, 400 MHz) δ 7.09 (d, 1H, J=7.3 Hz), 6.9-7.0 (m, 2H), 4.81 (s, 2H), 3.83 (s, 3H), 3.4-3.5 (m, 1H), 3.3-3.4 (m, 1H), 3.2- 3.2 (m, 1H), 3.00 (br s, 1H), 2.83 (br d, 1H, J=9.0 Hz), 2.6-2.7 (m, 2H), 2.19 (s, 3H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 17 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-fluoro-4-methoxyphenyl)prop-2-yn- 1-yl) oxime (17): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.5% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 289.37.1H NMR (METHANOL-d4, 400 MHz) δ 7.1-7.2 (m, 2H), Docket No.: 367605.00005 7.07 (t, 1H, J=8.7 Hz), 4.79 (s, 2H), 3.90 (s, 3H), 3.3-3.4 (m, 1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.81 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -136.8 (s). Example 18 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-chloro-4-methoxyphenyl)prop-2-yn- 1-yl) oxime (18): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.8% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 305.34.1H NMR (METHANOL-d4, 400 MHz) δ 7.43 (d, 1H, J=2.0 Hz), 7.36 (dd, 1H, J=2.2, 8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 4.80 (s, 2H), 3.91 (s, 3H), 3.3-3.5 (m, 1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.80 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 19 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-methyl-4-methoxyphenyl)prop-2- yn-1-yl) oxime (19): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.6% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 285.40.1H NMR (METHANOL-d4, 400 MHz) δ 7.26 (dd, 1H, J=2.0, 8.3 Hz), 7.20 (s, 1H), 6.87 (d, 1H, J=8.3 Hz), 4.79 (s, 2H), 3.84 (s, 3H), 3.3-3.5 (m, 1H), 3.3-3.3 (m, 1H), 3.1-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.80 (br d, 1H, J=9.5 Hz), 2.6-2.7 (m, 2H), 2.17 (s, 3H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 20 Docket No.: 367605.00005 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-fluoro-4-chloro-phenyl)prop-2-yn-1- yl) oxime (20): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.7% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 293.30.1H NMR (METHANOL-d4, 400 MHz) δ 7.47 (t, 1H, J=7.9 Hz), 7.33 (dd, 1H, J=1.7, 9.8 Hz), 7.25 (d, 1H, J=8.3 Hz), 4.81 (s, 2H), 3.4-3.5 (m, 1H), 3.3- 3.4 (m, 1H), 3.2-3.3 (m, 1H), 2.9-3.1 (m, 1H), 2.81 (br d, 1H, J=9.5 Hz), 2.6-2.8 (m, 2H), 2.0- 2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -117.1 (s). Example 21 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-fluoro-3-chloro-phenyl)prop-2-yn-1- yl) oxime (21): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.7% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 293.30.1H NMR (METHANOL-d4, 400 MHz) δ 7.57 (dd, 1H, J=2.0, 7.1 Hz), 7.41 (ddd, 1H, J=2.0, 4.6, 8.6 Hz), 7.25 (t, 1H, J=8.9 Hz), 4.81 (s, 2H), 3.4-3.5 (m, 1H), 3.3-3.5 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0- 2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -115.7 (s). Example 22 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-difluoromethoxy-phenyl)prop-2-yn- 1-yl) oxime (22): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.1% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 307.20.1H NMR (CHLOROFORM-d, 400 MHz) δ 7.3-7.3 (m, 2H), 7.1-7.1 (m, 1H), 7.0-7.1 (m, 1H), 6.50 (t, 1H, J=76 Hz), 4.82 (s, 2H), 3.58 (br d, 1H, J=17.4 Hz), 3.2-3.4 (m, 2H), 3.0-3.2 (m, 1H), 2.85 (br d, 1H, J=9.5 Hz), 2.7-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.8 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -80.9 (s). Example 23 Docket No.: 367605.00005 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-pyridyl)prop-2-yn-1-yl) oxime (23): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 242.37.1H NMR (METHANOL-d4, 400 MHz) δ 8.54 (d, 2H, J=5.9 Hz), 7.45 (d, 2H, J=4.9 Hz), 4.86 (s, 2H), 3.4-3.5 (m, 1H), 3.4-3.4 (m, 1H), 3.1-3.2 (m, 1H), 2.9-3.1 (m, 1H), 2.81 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 24 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(1-methyl-3-pyrazolyl)prop-2-yn-1-yl) oxime (24): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 245.39.1H NMR (METHANOL-d4, 400 MHz) δ 7.59 (d, 1H, J=2.2 Hz), 6.40 (d, 1H, J=2.2 Hz), 4.80 (s, 2H), 3.89 (s, 3H), 3.4-3.5 (m, 1H), 3.3-3.3 (m, 1H), 3.19 (d, 1H, J=4.2 Hz), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Example 25 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(1-methyl-4-pyrazolyl)prop-2-yn-1-yl) oxime (25): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 245.39.1H NMR (METHANOL-d4, 400 MHz) δ 7.77 (s, 1H), 7.55 (s, 1H), 4.77 (s, 2H), 3.88 (s, 3H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 1H), 3.19 (d, 1H, J=4.2 Hz), 2.9-3.0 (m, 1H), 2.78 (br d, 1H, J=9.3 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H). Docket No.: 367605.00005 Example 26 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-trifluoromethoxy-phenyl)prop-2-yn- 1-yl) oxime (26): 96.3% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 325.20.1H NMR (CHLOROFORM-d, 400 MHz) δ 7.3-7.4 (m, 3H), 7.18 (td, 1H, J=1.1, 8.1 Hz), 4.81 (s, 2H), 3.43 (s, 1H), 3.2-3.3 (m, 2H), 2.9-3.0 (m, 1H), 2.74 (br d, 1H, J=9.5 Hz), 2.5-2.6 (m, 2H), 1.9-2.0 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (CHLOROFORM-d, 400 MHz) δ -57.8 (s). Example 27 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(3-fluoromethoxy-phenyl)prop-2-yn-1- yl) oxime (27): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.5% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 280.20.1H NMR (CHLOROFORM-d, 400 MHz) δ 7.2-7.3 (m, 1H), 7.2-7.2 (m, 2H), 7.0-7.1 (m, 1H), 5.70 (d, 2H, J=54.2 Hz), 4.82 (s, 2H), 3.4-3.5 (m, 1H), 3.2- 3.3 (m, 2H), 2.9-3.0 (m, 1H), 2.75 (br d, 1H, J=9.5 Hz), 2.5-2.6 (m, 2H), 1.9-2.1 (m, 1H), 1.6- 1.7 (m, 1H).19F NMR (CHLOROFORM-d, 400 MHz) δ -148.8 (s). (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(2-trifluoromethoxy-phenyl)prop-2-yn- 1-yl) oxime (28): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.3% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 325.20.1H NMR (CHLOROFORM-d, 400 MHz) δ 7.52 (dd, 1H, Docket No.: 367605.00005 J=1.6, 7.9 Hz), 7.3-7.4 (m, 1H), 7.2-7.3 (m, 2H), 4.85 (s, 2H), 3.4-3.5 (m, 1H), 3.2-3.3 (m, 2H), 2.9-3.0 (m, 1H), 2.77 (br d, 1H, J=9.5 Hz), 2.5-2.7 (m, 2H), 1.9-2.0 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (CHLOROFORM-d, 400 MHz) δ -57.4 (s). Example 29 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-difluoromethoxy-phenyl)prop-2-yn- 1-yl) oxime (29): 99.1% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.0% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 307.37.1H NMR (METHANOL-d4, 400 MHz) δ 7.4-7.5 (m, 2H), 7.1-7.2 (m, 2H), 6.88 (t, 1H, J=76 Hz), 4.81 (s, 2H), 3.54 (s, 1H), 3.4-3.5 (m, 1H), 3.3-3.3 (m, 1H), 2.9-3.0 (m, 1H), 2.79 (br d, 1H, J=9.8 Hz), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -83.8 (s). Example 30 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(5-methoxy-4-fluoro-3-chloro- phenyl)prop-2-yn-1-yl) oxime (30): 89.5% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 98.2% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 323.12.1H NMR (METHANOL-d4, 400 MHz) δ 7.11 (ddd, 2H, J=1.8, 6.9, 9.1 Hz), 4.81 (s, 2H), 3.89 (s, 3H), 3.4-3.6 (m, 1H), 3.3-3.5 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6- 1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -136.9. Example 31 Docket No.: 367605.00005 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(5-methoxy-4-fluoro-2-fluoro- phenyl)prop-2-yn-1-yl) oxime (31): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 307.17.1H NMR (METHANOL-d4, 400 MHz)δ 7.16 (dd, 1H, J=6.6, 9.3 Hz),� 7.02-7.05 (m, 1H), 4.81 (s, 2H), 3.85 (s, 3H), 3.4-3.5 (m, 1H),3.3-3.5 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -118.9, -129.5. Example 32 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-fluoro-3,5-dichloro-phenyl)prop-2- yn-1-yl) oxime (32): 100% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 99.3% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 327.34.1H NMR (METHANOL-d4, 400 MHz) δ 7.53 (d, 2H, J=6.4 Hz), 4.80 (s, 2H), 3.4-3.5 (m, 1H), 3.3-3.5 (m, 1H), 3.2-3.2 (m, 1H), 2.9-3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL- d4, 400 MHz) δ -116.9. Example 33 (R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(3-(4-methoxy-3,5-difluoro-phenyl)prop- 2-yn-1-yl) oxime (33): 94.5% pure by HPLC (column: Zorbax SB-CN; 250 × 4.6 mm, 5 μm); 100% Z by HPLC (column: Waters Xbridge C18: 150 × 4.6 mm, 5 μm; UV detection at 254 nm). MS-ESI (m / z): [M+H]+= 307.17.1H NMR (METHANOL-d4, 400 MHz) δ 7.09 (d, 2H, J=8.2 Hz), 4.81 (s, 2H), 4.00 (s, 3H), 3.4-3.5 (m, 1H), 3.3-3.5 (m, 1H), 3.2-3.2 (m, 1H), 2.9- 3.0 (m, 1H), 2.8-2.8 (m, 1H), 2.6-2.7 (m, 2H), 2.0-2.1 (m, 1H), 1.6-1.7 (m, 1H).19F NMR (METHANOL-d4, 400 MHz) δ -130.3. 3. Preparation of Compounds 34-44 Docket No.: 367605.00005 Compound 34 through Compound 44 have been or can be prepared by following the general synthesis Scheme 3 (Tecle, H., et al., J. Med. Chem.1998, 41, 2524; Schwindt, M. A. et al., US 6121459, WO98 / 32758). 4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2-ol: To a solution of Pd(PPh3)4(0.05 equiv.), CuI (0.12 equiv.), Et3N (1.0 equiv.) in THF (10 V), 2-methylbut-3-yn-2-ol (3.0 equiv.) and 1-fluoro-4-iodo-2-methoxybenzene (1.0 equiv.) were added sequentially under N2. After stirring at 80 ℃ for 16 h, the reaction mixture was cooled, filtered through a pad of celite. EtOAc and water were added. The organic layer was separated, dried, concentrated and the residue was purified via column chromatography to afford the title compound in 62% yield. Docket No.: 367605.00005 2-((4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2-yl)oxy)isoindoline-1,3-dione: To a solution of 4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2-ol (1.0 equiv.), 2- hydroxyisoindoline-1,3-dione (1.0 equiv.), PPh3(1.0 equiv.) in THF (30 V), DEAD (1.1 equiv.) was added dropwise at 0 ℃. The reaction mixture was then stirred at 25 ℃ for 16 hours and concentrated to dryness. EtOH was added and the solid precipitate was collected by filtration to afford the title compound in 25% yield. O-(4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2-yl)hydroxylamine: To a solution of 2-((4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2-yl)oxy)isoindoline-1,3-dione in THF (5V), N2H4CH3 (3 equiv.) was added dropwise at 25 ℃. After stirring at 25 ℃ for 1 hour, the reaction mixture was partitioned between DCM and water. The organic layer was separated, dried, and concentrated to afford the title compound in 56% yield. Z / E-(R)-isomer (Z / E)-(4R)-1-azabicyclo[2.2.1]heptan-3-one O-(4-(4-fluoro-3-methoxyphenyl)-2- methylbut-3-yn-2-yl) oxime (34): O-(4-(4-fluoro-3-methoxyphenyl)-2-methylbut-3-yn-2- yl)hydroxylamine (1.0 equiv.) and (R)-1-azabicyclo[2.2.1]heptan-3-one were dissolved in water (20 V). After stirring at 25 ℃ for 16 hours, the aqueous layer was extracted with DCM. The organic layers were combined, dried, and concentrated to afford the title compound (34). Example 35 Docket No.: 367605.00005 The Z / E isomers (Example 34) were separated via preparative HPLC to obtain (R)-(-)-Z- isomer compound (4R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(4-(4-fluoro-3- methoxyphenyl)-2-methylbut-3-yn-2-yl) oxime (35): MS-ESI (m / z): [M+H]+= 317.38. Example 36 (1S,4R)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-((S)-4-(4-fluoro-3-methoxyphenyl)but-3- yn-2-yl) oxime (36): MS-ESI (m / z): [M+H]+= 303.21. Example 37 (4R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(1-((4-fluoro-3- methoxyphenyl)ethynyl)cyclobutyl) oxime (37): MS-ESI (m / z): [M+H]+= 329.19. Example 38 (4R)-(−)-(Z)-1-azabicyclo[2.2.1]heptan-3-one O-(1-((4-fluoro-3- methoxyphenyl)ethynyl)cyclopentyl) oxime (38): MS-ESI (m / z): [M+H]+= 343.38. Examples 39-44 The following compounds 39-44 can be prepared and are being prepared, following the general synthetic Scheme 3 above. Docket No.: 367605.00005 BIOLOGICAL ASSAYS M1, M3, M5 FLIPR assay protocol Day 1: Cell seeding 1. Culture CHO-K1 / M1 or M3, M5 cells with F12 medium (10% FBS). 2. When cells reach 80% confluence, dissociate cells with 0.25% Trypsin-EDTA. 3. Measure cell density and dilute the cells to 5x10e5 / ml cells with F12 medium (10% FBS). 4. Dispense 30µl cells into each well (15,000 cells per well) of Matrigel coated 384-well plate (corning 3764#) with Multi-drop and culture at 37℃, 5% CO2 for 20hrs. Day 2: Cell based FLIPR assay procedure 5. Dilute test compounds with DMSO to 400X stock solution in 384-well (PE 6008590#) plate. 6. Transfer 1μl compound solution from step 5 to 43.4ul assay buffer to make 9X working solutions in 384-well plate by Bravo. 7. Add 10ul per well 4X Fluo 8 solution into cell plate. Incubate at 37°C, 5% CO2 in dark for 0.5h. 8. FLIPR transfer 5μl of 9X working solutions from step 6 into cell plate. 9. Read with FLIPR at room temperature using the specified settings and save data. M2, M4 cAMP assay protocol Procedures for Cell Suspension Preparation 1. Thaw frozen cells very briefly in a 37°C water bath under sterile conditions until just before ice completely melt (for about 1 minute) with a continuous agitation. Caution: Longer incubation may result in cell death. 2. Remove DMSO from the media by carefully transferring thawed cells to a sterile 15 / 50 Docket No.: 367605.00005 mL tube, filling tube with 10-50mL of complete media pre-warmed to 37°C. Allow cells to sit 5min before centrifuge. Then centrifuge at 900 rpm for 5 minutes to pellet cells. 3. Resuspend cells with assay buffer. Procedures for cAMP Assay 1. Compound preparation: prepare compound addition plates in advance of assay. Prepare 1000X concentration of compound working solutions according to the plate layout. 2. Cell preparation: cell suspensions are prepared according to procedures described above before running the assay. 3. Compound addition: add 10 nL / well of working concentration of 1000X compound to low-volume 384 white assay plate with Echo. 4. Cell addition: Add 5 µL of 2X cell suspensions to each well of the assay plate which already contains compound. Seal the plate and incubate at 37℃ for 15 minutes. 5. Add 5 µL 2X EC80 of forskolin (0.4 µM) to each well of the assay plate. Seal the plate and incubate at 37℃ for 30 minutes. 6. Add 5 µL cAMP Eu-cryptate working solution to each well of the assay plate. 7. Add 5 µL Anti cAMP-d2 working solution to each well of the assay plate. Cover the plate with lid. Incubate at room temperature for 1 hours. 8. Read the fluorescence at 665 and 615 nm with EnVision plate reader with TRF LASER using the specified settings and save data. Microsomal Stability Study Protocol Procedure: 1. Preparation of Solutions Test compound was weighed and dissolved in 100% DMSO to get 10 mM stock solution. The stock solution was diluted to 500 μM with mixture of acetonitrile and H2O (1:1). Stock solutions of testosterone, warfarin, and propranolol were prepared at a concentration of 10 mM in 100% DMSO, respectively. The stock solution for each compound was diluted into 500 μM with mixture of acetonitrile and H2O (1:1). The final concentrations of DMSO and acetonitrile were equal or less than 0.1%. 2. Microsomal Incubations Docket No.: 367605.00005 Liver microsome incubations were conducted in duplicate in 96-well plates. Each well contains 40 µL of 0.1M potassium phosphate buffer (pH 7.4), 4.125 mM MgCl2, 0.625 mg / mL liver microsomes, and test compound (1.25 μM) or positive control. After 5-min preincubation at 37◦C, 10 µL of 5.0 mM NADPH in 0.1M potassium phosphate buffer was added to initiate the enzymatic reaction. The final component concentrations are 0.1M potassium phosphate buffer (pH 7.4), 1.0 mM NADPH, 3.3 mM MgCl2, 0.5 mg / mL liver microsomes, and test compound (1.0 μM) or positive control (1.0 μM). Reactions were terminated at various time points (0, 15, 60 min) by adding 100 µL of ice-cold acetonitrile containing internal standard. A parallel incubation was performed using 0.1M potassium phosphate buffer (pH 7.4) instead of NADPH as the negative control, and reactions was terminated at 60 min after incubation at 37°C. Data Analysis: LC-MS / MS was used for data analysis. The peak area ratio of test compound to internal standard will be plotted as a percentage of the relevant zero time point control (%Remained) for each reaction. The rate of metabolism (k) is the slope of the linear regression from log percentage remaining versus incubation time. The in vitro T1 / 2is calculated as -0.693 / k. The calculated rate was used to extrapolate the in vivo parameters: Intrinsic clearance (Clint) = k / c, where c is the microsomal protein concentration (0.5 mg / mL for liver microsomes); For human, apparent clearance (Clapp) = Clint*a*b / d (mL / min / kg), where a, b, and d are the scaling factors for normalizing Clint to human body weight. The scaling factors a = 45 mg / g (microsomal protein / liver weight), b / d= 20 g / kg (liver weight / body weight); Hepatic clearance (Clh) = (Clapp*Q) / Clapp+ Q), where Q = 20.7 mL / min / kg (liver blood flow); Hepatic extraction ratio (Eh) = (Clh / Q)*100 (%). For cynomolgus monkey, apparent clearance (Clapp) = Clint*a*b / d (mL / min / kg), where a, b, and d are the scaling factors for normalizing Clintto human body weight. The scaling factors a = 45 mg / g (microsomal protein / liver weight), b / d = 30 g / kg (liver weight / body weight); Hepatic Docket No.: 367605.00005 clearance (Clh) = (Clapp*Q) / Clapp + Q), where Q = 43.6 mL / min / kg (liver blood flow); Hepatic extraction ratio (Eh) = (Clh / Q)*100 (%). For beagle dog, apparent clearance (Clapp) = Clint*a*b / d (mL / min / kg), where a, b, and d are the scaling factors for normalizing Clint to human body weight. The scaling factors a = 45 mg / g (microsomal protein / liver weight), b / d= 32 g / kg (liver weight / body weight); Hepatic clearance (Clh) = (Clapp*Q) / Clapp+ Q), where Q = 30.9 mL / min / kg (liver blood flow); Hepatic extraction ratio (Eh) = (Clh / Q)*100 (%). For SD rat, apparent clearance (Clapp) = Clint*a*b / d (mL / min / kg), where a, b, and d are the scaling factors for normalizing Clintto SD Rat body weight. The scaling factors a = 45 mg / g (microsomal protein / liver weight), b / d= 40 g / kg (liver weight / body weight); Hepatic clearance (Clh) = (Clapp*Q) / Clapp + Q), where Q = 55.2mL / min / kg (liver blood flow); Hepatic extraction ratio (Eh) = (Clh / Q)*100 (%). For CD-1 mouse, apparent clearance (Clapp) = Clint*a*b / d (mL / min / kg), where a, b, and d are the scaling factors for normalizing Clint to human body weight. The scaling factors a = 45 mg / g (microsomal protein / liver weight), b / d= 88 g / kg (liver weight / body weight); Hepatic clearance (Clh) = (Clapp*Q) / Clapp+ Q), where Q = 90 mL / min / kg (liver blood flow); Hepatic extraction ratio (Eh) = (Clh / Q)*100 (%). Testing Results The assay results for Compounds 1-8 on M1-M5 receptor subtypes are listed in Table 1. Table 1. Functional Agonism Data on M1-M5 Receptor Subtypes Docket No.: 367605.00005 Note: CNBD: Can not be determined In comparison with compound 1, compounds 3, 5 and 7 maintain M1 and M4 selectivity over M2, M3 and M5. In addition, deuteration at the different position of the molecule yielded unexpected, significant difference on the functional cellular potency, consistently in the M1 / M3 / M5 FLIPR assay and the M2 / M4 cAMP assay. The metabolic stability testing results for compounds 1, 3, 5, and 7 on various species are listed in Table 2. Table 2. Metabolic Stability in Liver Microsomes • No significant difference on metabolic stabilities of compound 3, 5, and 7 from compound 1 for all species tested. The assay results for Compounds 9-29 on M1-M5 receptor subtypes are listed in Table 3. Table 3. Functional Agonism Data on M1-5 Receptor Subtypes Docket No.: 367605.00005 Docket No.: 367605.00005 Docket No.: 367605.00005 The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All patent or non-patent references mentioned herein are incorporated by reference in their entireties without admission of them as prior art.

Claims

Docket No.: 367605.00005 CLAIMS What is claimed is:

1. A method of treating a neuropsychiatric disorder associated with muscarinic 4 and / or muscarinic 1 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6 alkyl and C1-6 haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6alkyl, deuterated C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 6-membered heterocyclyl, C6-10aryl, and 5- to 10- membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8 cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4 alkoxy, C1-4 haloalkyl, and C1-4 haloalkoxy;Docket No.: 367605.00005 R7at each occurrence is independently selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, and C1-6 haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6 alkyl; and Rcand Rdare independently H or C1-4 alkyl. The method of claim 1, wherein the ring Ar is selected from:The method of claim 1 or 2, wherein:m is 0, 1, or 2; R1ais hydrogen or C1-4alkyl;Docket No.: 367605.00005 R1at each occurrence is independently hydrogen, deuterium, halogen, C1-4 alkyl, C1-4 haloalkyl, CN, OR7; R3and R4are independently selected from C1-4alkyl, deuterated C1-4alkyl, C1-4haloalkyl, C3-6 cycloalkyl, and phenyl; or R3and R4together with the carbon atom to which they are attached form C3-6 cycloalkyl or 3- to 6-membered heterocyclyl; and R7at each occurrence is independently selected from H, deuterium, C1-4alkyl, deuterated C1-4alkyl, and C1-4haloalkyl. The method of any one of claims 1 to 3, wherein the compound of formula (I) is a compound of formula (II):The method of any one of claims 1 to 4, wherein the compound of formula (I) is a compound of formula (II-1):or an isomer, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, 2, 3; n is 0 or 1; R1at each occurrence is independently selected from hydrogen, deuterium, chlorine, bromine, fluorine, OH, OCHF2, OCF3, CHF2, CF3, OMe, and OCD3; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-4alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or - CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2);Docket No.: 367605.00005 R5and R6are each independently hydrogen or deuterium; and R7is C1-4 alkyl or deuterated C1-4 alkyl.

6. The method of claim 5, wherein the compound of formula (II-1) is selected from7 The method of any one of claims 1-3, wherein the compound of formula (I) is selected from Examples 9 to 44, or an isomer, or a pharmaceutically acceptable salt thereof. 8 The method of any one of claims 1 to 13, wherein neuropsychiatric disorder is selected from schizophrenia, bipolar disorder, and related conditions such as, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders. 9 A compound of formula (I):or an isomer, or a pharmaceutically acceptable salt thereof, wherein: ring Ar is phenyl or 5- or 6-membered heteroaryl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2;Docket No.: 367605.00005 R1at each occurrence is independently selected from hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd, wherein the C1-6alkyl and C1-6haloalkyl are each optionally substituted by CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-6 alkyl, C1-6 haloalkyl, C3-6cycloalkyl, 3- to 6-membered heterocyclyl, C6-10aryl, and 5- to 10-membered heteroaryl; or R3and R4together with the carbon atom to which they are attached form a C3-8cycloalkyl, 3- to 8-membered heterocyclyl; or R3and R4together are oxo, wherein any said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one, two, three substituents independently selected from halogen, C1-4alkyl, C1-4haloalkyl, CN, nitro, OR7, S(O)iR8(i = 0, 1, or 2), C(O)R8, OC(O)R8, CO2R7, NHC(O)R8, NRaRb, and CONRcRd; R5and R6are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-4 alkoxy, C1-4haloalkyl, and C1-4haloalkoxy; R7at each occurrence is independently selected from H, deuterium, C1-6alkyl, deuterated C1-6alkyl, and C1-6 haloalkyl; R8is C1-6alkyl; Raand Rbare independently H or C1-6alkyl; and Rcand Rdare independently H or C1-4 alkyl, with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) if m is 1, then R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) if m is 2, then the two R1are not both Cl, CF3, or OCH3. The compound of claim 9, wherein the ring Ar is selected from:Docket No.: 367605.00005The compound of claim 9 or 10, wherein: the ring Ar is selected fromm is 0, 1, or 2; R1ais hydrogen or C1-4 alkyl; R1at each occurrence is independently hydrogen, deuterium, halogen, C1-4alkyl, C1-4haloalkyl, CN, OR7; R3and R4are independently selected from C1-4 alkyl, deuterated C1-4 alkyl, C1-4 haloalkyl, C3- 6 cycloalkyl, and phenyl; or R3and R4together with the carbon atom to which they are attached form C3-6cycloalkyl or 3- to 6-membered heterocyclyl; and R7at each occurrence is independently selected from H, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, and C1-4 haloalkyl, with the provisos that when ring Ar is phenyl, n is 0, and R3to R6are all hydrogen, then: (i) m is not 0; (ii) when m is 1, R1is not hydrogen, F, Cl, CH3, CF3, or OCH3; and (iii) when m is 2, the two R1are not both Cl, CF3, or OCH3. The compound of any one of claims 9-11, wherein the compound of formula (I) is selected from Examples 3 to 44, or an isomer, or a pharmaceutically acceptable salt thereof.Docket No.: 367605.00005 13. The compound of claim 9, having a structure of formula (II-1):or an isomer, or a pharmaceutically acceptable salt thereof, wherein: j is 0, 1, 2, 3; n is 0 or 1; R1at each occurrence is independently selected from hydrogen, deuterium, chlorine, bromine, fluorine, OH, OCHF2, OCF3, CHF2, CF3, OMe, and OCD3; R2at each occurrence is independently selected from hydrogen, deuterium, halogen, and oxo; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1- 4 alkyl, and C1-4haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or - CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j is not more than 2) ; R5and R6are each independently hydrogen or deuterium; and R7is C1-4alkyl or deuterated C1-4alkyl; and wherein at least one of R1to R6is deuterium or comprises a deuterium substituent. 4 The compound of claim 13, or an isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula III:wherein: R1at each occurrence is independently hydrogen or deuterium; R3and R4are each independently selected from hydrogen, deuterium, C1-4 alkyl, deuterated C1- 4 alkyl, and C1-4haloalkyl; or R3and R4together form -CH2(CH2)kCH2- (k is 0, 1, 2, or 3) or - CH2(CH2)iO(CH2)jCH2- (i and j are independently 0, 1, or 2, provided that the sum of i + j isDocket No.: 367605.00005 not more than 2); and R7is C1-4 alkyl or deuterated C1-4 alkyl; and wherein at least one of R1, R3, and R4is deuterium, or R7is deuterated C1-4alkyl.

15. The compound of claim 13 or 14, or an isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. A pharmaceutical composition comprising a compound according to any one of claims 9 to 15, or an isomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A method for treating a neuropsychiatric disorder associated with muscarinic 1 and / or muscarinic 4 receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 9 to 15, or an isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 16.

18. The method of claim 17, wherein the neuropsychiatric disorder is selected from schizophrenia, bipolar disorder, and related conditions such as, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders.

19. Use of a compound according to any one of claims 9 to 15, or an isomer, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a neuropsychiatric disorder.

20. The use of claim 19, wherein the neuropsychiatric disorder is selected from schizophrenia, bipolar disorder, and related conditions such as, but not limited to, agitation and psychotic symptoms in neurodegenerative disorders.

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